HETEROCYCLES

Review | Regular issue | Vol. 85, No. 8, 2012, pp. 1821-1867
Received, 17th March, 2012, Accepted, 26th April, 2012, Published online, 1st May, 2012.
DOI: 10.3987/REV-12-738

■ Design and Synthesis of Novel Opioid Ligands and Their Pharmacologies

Hiroshi Nagase* and Hideaki Fujii

School of Pharmaceutical Sciences, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan

Abstract

We describe the recent progress of our investigations in the opioid field in this review, which includes interesting reactions using naltrexone derivatives and pharmacological properties of the synthesized derivatives. Some reactions utilized the characteristic structural features of the morphinan skeleton, and others were applicable to general compounds. Some derivatives were expected to be lead compounds for developing novel ligands selective for the individual opioid receptor types. Triplet drugs consisting of three pharmacophore units in one molecule exhibited interesting pharmacological profiles and would be expected to be a useful tool for clarifying the pharmacology of receptor oligomerization.

CONTENTS
1. Introduction
2. Brief Summary of a Previous Review
3. Synthesis of (–)-Homogalanthamine from Naltrexone
4. A Novel Rearrangement Reaction for the Synthesis of New Opioid Ligands with Oxazatricyclodecane Structure
4-1. A Novel κ Agonist KNT-63 with an Oxabicyclo[2.2.2]octane Skeleton
4-2. Rearrangement Reaction of 4,5-Epoxymorphinan Derivatives with Carbamoylepoxy Rings
5. Investigation of the Beckett–Casy Model
5-1. Beckett–Casy Model
5-2. Synthesis of 16,17-seco-Naltrexone Derivatives and Their Binding Profiles for Opioid Receptor Types
5-3. Synthesis of 15-16 Nornaltrexone Derivatives and Their Binding Profiles for Opioid Receptor Types
5-4. Synthesis of Naltrexone Derivatives with Contracted or Expanded D-Rings and Their Binding Profiles for Opioid Receptor Types
6. Synthesis of Triplet Drugs with 1,3,5-Trioxazatriquinane Skeletons and their Pharmacologies
6-1. New Synthetic Method of the Key Intermediate α-Hydroxyaldehyde
6-2. Synthesis of Symmetrical and Nonsymmetrical Triplet Drugs with Morphinan Skeletons and Their Pharmacologies
6-3. Synthesis of Capped Homotriplet Drugs with Morphinan Skeletons and Their Pharmacologies
7. Synthesis of Propellane Derivatives with Affinities for Opioid Receptors
8. Concluding Remarks


1. INTRODUCTION
Opioids are generally classified into three types (µ, δ, and κ types) not only by pharmacological studies but also by molecular biological characterizations,1 and all receptor types are related to analgesic effects. Narcotic addiction is believed to be derived from the µ receptor type, and therefore δ and κ types are promising drug targets for analgesics without addiction. To obtain ideal analgesics without addiction and other side effects derived from the µ receptor, we have synthesized various kinds of naltrexone derivatives and reported selective ligands for the κ2 and δ receptors.3 In 2009, one of our designed κ selective agonists, TRK-820 (nalfurafine (1) hydrochloride, Figure 1), was launched in Japan as an antipruritic for patients undergoing dialysis.2a,b,e Although many arylacetamide derivatives such as U-50,488H (2)4 and U-69,593 (3)5 (Figure 1) were synthesized and developed as κ agonists, all of these derivatives were eliminated from clinical trials as not only analgesics but as antipruritics because of their serious side effects like psychotomimetic and aversive reactions.6 On the other hand, nalfurafine (1) has neither aversive nor addictive effects.7 The pharmacological differences between nalfurafine (1) and arylacetamide derivatives have been attributed to the differences in their affinities for κ receptor subtypes (κ1 and κ3)8 (arylacetamide derivatives target κ18b,c and nalfurafine (1) targets κ38d–f).
Although many δ agonists have also been studied as analgesics,9 antidepressant,9a,10 and antipollakiuria,11 no derivatives represented by SNC-8012 (4, Figure 2) have yet been launched, perhaps due to weak activity and/or serious side effects like convulsion9a,10 and catalepsy.13 We also synthesized a δ agonist, TAN-673a,b,14 (5, Figure 2), which showed selective δ agonist activity and analgesic effects without convulsion and catalepsy, but its agonist activity, especially analgesic activity, was weak. Therefore, none

of the in vivo pharmacological effects via the δ receptor have been sufficiently confirmed except analgesia. Quite recently, we designed and synthesized the potent δ agonists, SN-28 (6)3c and KNT-127(7)3d,15 (Figure 2). Although subcutaneously injected SN-28 (6) showed almost no analgesic activity, s.c. administration of KNT-127 (7) showed a 30-fold more potent analgesic activity than did TAN-67 (5).3d In the course of investigating the design and synthesis of many opioid derivatives, including the aforementioned agonists by using naltrexone (8, Figure 3) as a starting material, we found many interesting reactions. Some of them have already been reported in a review article.16 In the present review, we will describe our recent progress after a brief summary of the previous review.

2. BRIEF SUMMARY OF A PREVIOUS REVIEW
The previous review16 included eight reactions that are summarized in Scheme 1. The 14-OH group plays an essential role in providing the products in the reactions shown by equations (1) – (4), (5') and (7). In the reactions depicted by equations (2) and (2'), (5) and (5'), and (6) and (7), the presence or absence of the 4,5-epoxy bridge decisively influences the reaction course. The reactions indicated by equations (5'), (7), and (8) are novel rearrangement reactions. Stereoelectronic effects were observed in the reactions shown by (3) and (5'). Novel trimer 25 (equation (6)) was prepared with the anticipation that the compound would elicit unique pharmacological effects and would serve as a useful pharmacological tool.

3. SYNTHESIS OF (–)-HOMOGALANTHAMINE FROM NALTREXONE
(–)-Galanthamine (30, Figure 4)17 was isolated from the Caucasian snowdrop, Galanthus woronowii, and also from another species of the Amaryllidaceae family, Lycoris radiate. It is an acetylcholinesterase (AChE) inhibitor18 and a prescription drug for the treatment of Alzheimer’s disease in Europe and the United States.19 There are many reports describing the syntheses of galanthamine (30)20 and its derivatives,20a including C-ring,21 D-ring,22 quaternary ammonium, and bis-interacted derivatives.23 However, to the best of our knowledge, the synthesis of (–)-homogalanthamine (31, Figure 4) has not yet been reported. We attempted to synthesize (–)-homogalanthamine (31) from the µ opioid antagonist naltrexone (8)24 because they share common structural features (Figure 4). We were also interested in whether a transformation from 8 to 31 would impact the pharmacological effects of 31 on either the AChE or the opioid receptors.
We started this synthesis from O-methylation of naltrexone (8), followed by the reduction of the ketone in 32 with NaBH(OAc)3 in AcOH to give 6α-alcohol 33 (Scheme 2). After the mesylation of 33, the obtained mesylate 34 was treated with NaI in DMF at 100 ºC, followed by elimination of hydrogen iodide with DBU to afford olefins 35 and 36 in 2 steps with respective yields of 65% and 9%. The resulting olefins were hydrogenated in the presence of Wilkinson’s catalyst to give deoxygenated compound 37

quantitatively. After an acetylation of 37, a treatment of the obtained acetate with 2,2,2-trichloroethyl chloroformate (Troc-Cl) and K2CO3 in 1,1,2,2-tetrachloroethane (TCE) at 150 ºC provided the carbamate, which was hydrolyzed with KOH in DMSO at 110 ºC to give 38.3d The resulting amine 38 was chlorinated with NCS in CHCl3 at -30 ºC to give N-chloroamine 39.25a,26
The Grob fragmentation25 of N-chloroamine 39 was a key reaction in our synthesis of (–)-homogalanthamine (31) from naltrexone (8) (Scheme 3). The Grob fragmentation of 39 under the conditions of NaH in THF proceeded very slowly and the degradation of 39 concomitantly occurred during the reaction. The addition of 15-crown-5 to the reaction mixture effectively facilitated the reaction rate and the fragmentation was complete within five minutes. The Grob fragmentation followed by reduction of the resulting imine with LiBH4 afforded a mixture of hemiaminal 40 and amine 41 in quantitative yield. The mixture was treated with ClCO2Me, which simultaneously opened the five-membered hemiaminal ring in 40 and protected the nitrogen to give ketocarbamate 42. The treatment 41 with ClCO2Me and subsequent hydrolysis of the obtained carbonate provided alcohol 43, which was oxidized with PCC to give ketocarbamate 42 in 4 steps from 39.
In the final stage of the synthesis (Scheme 4), ketocarbamate 42 reacted with LDA and PhSSPh, followed

by mCPBA oxidation and then was heated in the presence of NaHCO3 under reflux in toluene to give α,β-unsaturated ketone 44. The Luche reduction27 of 44 at -78 ºC afforded a mixture of desired allylic alcohol 45a (76%) and its epimer 45b (14%). After the separation of allylic alcohol mixture 45, α-isomer 45a was acetylated and then the PdCl2(MeCN)2-catalyzed [3.3]sigmatropic rearrangement of the obtained acetate provided rearranged acetate 46 in 97% (2 steps yield).28 The reduction of the carbamate and acetate moieties in 46 with LiAlH4 gave the objective (–)-homogalanthamine 31. Demethylation of 31 with dodecanethiol and t-BuOK in DMF afforded crystalline phenol derivative 47, whose structure was confirmed by X-ray crystallography.
(–)-Homogalanthamine (31) showed inhibitory activity toward AChE (IC50 = 3.0 µM) and its potency was 5-fold less than that of galanthamine (30). Interestingly, demethylated compound 47 of (–) homogalanthamine (31) did not bind to any of the opioid receptor types at all. This result indicates that the C9–C14 bond (Figure 4) in naltrexone (8) is an important structural determinant for binding to all opioid receptor types.

4. A NOVEL REARRANGEMENT REACTION FOR THE SYNTHESIS OF NEW OPIOID LIGAND WITH OXAZATRICYCLODECANE STRUCTURE
4-1. A Novel κ Agonist KNT-63 with Oxabicyclo[2.2.2]octane Skeleton
On the basis of both the detailed structure-activity relationship (SAR) investigations of nalfurafine (1) derivatives and their conformational analyses,29 we developed the working hypothesis for an active conformation of 1 (Figure 5): the C-ring in 1 would assume the boat form to orient the 6-amide side chain toward the upper side of the C-ring when 1 bound to the κ receptor.2c,d,f Based on this hypothesis, we designed and synthesized 4,5-epoxymorphinan derivative KNT-63 (Figure 5) with an oxabicyclo[2.2.2]octane skeleton.2d KNT-63 showed strong binding affinities for the opioid receptors (Ki (µ) = 0.212 nM, Ki (δ) = 2.73 nM, Ki (κ) = 0.111 nM) in the competitive binding assays and produced a dose-dependent analgesic effect in the mouse acetic acid writhing test. The antinociceptive effect induced by KNT-63 was antagonized by κ antagonist nor-BNI but not by µ antagonist naloxone or δ antagonist NTI, indicating that KNT-63 is a κ agonist.
KNT-63 was prepared from O-methyl naltrexone (32)30 as shown by Scheme 5. Intermediates 48 were prepared using the Darzens condensation. After a separation, 6'α-isomer 48a was treated with aniline in the presence of strong base (n-BuLi or NaH) under reflux in THF to give 49 with the oxabicyclo[2.2.2]octane skeleton in 60% yield. Finally, O-demethylation of 49 with BBr3 afforded KNT-63.2d

4-2. Rearrangement Reaction of 4,5-Epoxymorphinan Derivatives with Carbamoylepoxy Rings
Although N-phenyl amide 49 was directly prepared from 4,5-epoxymorphinan with ethoxycarbonylepoxy ring 48a (Scheme 5), the analogues with various amide N-substituents were synthesized from 48 via 4,5-epoxymorphinan with the carbamoylepoxy ring (e.g., 50a in Scheme 6). Scheme 6 illustrates an example of N-benzyl derivative synthesis. Contrary to the case of aniline, ester-amide exchange reaction with a lithium amide, which was prepared from a more nucleophilic alkyl amine, smoothly proceeded at -78 ºC to enable isolation of carbamate 50a. The treatment of 50a in the presence of NaH under reflux in THF (bp: 66 ºC) provided intramolecular cyclization to give oxabicyclo[2.2.2]octane derivative 51 in 69% yield. For the purpose of improving the yield of 51, we attempted to carry out the intramolecular cyclization reaction at higher reaction temperature. Surprisingly, the reaction under the cyclopentyl methyl ether (CPME, bp: 106 ºC) reflux conditions did afford novel oxazatricyclodecane structure 52 in 81% yield without objective compound 51.31 The structure of 5232 was confirmed by NOESY experiments and X-ray crystallography. Compound 52 exhibited moderate binding affinities for the opioid receptor types (Ki (µ) = 47.7 nM, Ki (δ) = 174.6 nM, and Ki (κ) = 248.1 nM),33a indicating that compound 52 may be a lead compound for the development of novel opioid ligands.
We examined the progress of the rearrangement reaction under various reaction conditions. The treatment

of the solution of 50a in CPME with NaH at 60 ºC provided only compound 51 in 84% yield and compound 50a was recovered in 11% yield. This result indicated that the reaction temperature was an important factor in facilitating the rearrangement and that the oxabicyclo[2.2.2]octane derivative 51 could be an intermediate that could provide rearrangement compound 52. The reaction of 50a with t-BuOK in t-BuOH under reflux conditions also afforded 52 in 93%. It is worth noting that in spite of the strong basic reaction conditions no epimer 53 (Figure 6) was isolated in any of these reactions.
We examined the rearrangement reaction using amide 50b, the epimer of amide 50a, under both reaction conditions (condition A: NaH, CPME, reflux; condition B: t-BuOK, t-BuOH, reflux). Interestingly, each of the two reaction conditions afforded different products. Compound 53 was obtained in 91% yield under the condition A, whereas condition B provided rearrangement compound 52 in 89% yield. The results suggested that an epimerization occurred under condition B, but not under condition A. As mentioned above, amide 50a was converted into compound 52 under both reaction conditions (Scheme 7).
On the basis of the obtained results, we proposed a mechanism for the rearrangement reaction (Scheme 8). In the case of reaction conditions A, the irreversible deprotonation of 50a would proceed to give dianion A. The intramolecular cyclization would occurs through attack by the resulting alkoxide in A at the α- carbon of the amide group to provide oxabicyclo[2.2.2]octane intermediate B. The reaction would stop at this stage at a relatively low reaction temperature (e.g., a THF refluxing temperature). When the reaction temperature was sufficiently high (e.g., at the CPME or t-BuOH refluxing temperature), the rearrangement reaction would proceed. The alkoxide in B would facilitate a 1,2-shift of the C6–C7 bond with cleavage of the 4,5-epoxy bridge to give the intermediate ketone C. The amide and ketone moieties in C were located so close to each other that the subsequent cyclization could occur smoothly to afford

the rearrangement product 52. The dianion species prepared under the irreversible deprotonation conditions may prevent further deprotonation of the α-proton of the amide group. Therefore, no epimerization could be observed. On the other hand, the reversible deprotonation by t-BuOK in t-BuOH could permit deprotonation of the α-proton of the amide group. As a result, the epimerization could proceed to eventually give convergent product 52, regardless of the configuration of the amide group in 50a or 50b. Oxabicyclo[2.2.2]octane intermediate B was a key intermediate in the proposed mechanism. Indeed, the treatment of oxabicyclo[2.2.2]octane 51 under the rearrangement reaction conditions provided the rearrangement product 52 (Scheme 9). Although we proposed that the rearrangement from B to C would proceed by a 1,2-shift, a mechanism via amide enolate E (Scheme 10) could not be ruled out. However, the treatment of compound 54 with a hydroxymethyl group instead of an electron withdrawing amide group under the rearrangement reaction conditions gave a mixture of the corresponding rearrangement product 55 and ketone 56, acetylation of which provided compound 57 (Scheme 11). The result supports our proposed mechanism including a 1,2-shift.

5. INVESTIGATION OF THE BECKETT–CASY MODEL
5-1. Beckett–Casy Model
Beckett and Casy proposed a model for the interaction between the opioid receptor and a ligand like morphine.34 According to the Beckett–Casy model, (–)-morphine can bind the opioid receptor site by use of three pharmacophoric interactions; ionic, π–π (aromatic ring) interactions, and hydrogen bonding. Furthermore, the C15–C16 bond (green line) projecting in front of and to the side of the plane consisting of the A-ring and the basic nitrogen in morphine is proposed to fit into the receptor cavity moiety in this model (Figure 7). Because many structural skeletons have been applied to the Beckett–Casy model, the credibility of the Beckett–Casy model has been under discussion for a long time and a decisive conclusion has not yet been reached. Therefore, we attempted to synthesize 16,17-seco-naltrexone derivatives 58 (Figure 7) by use of C16–N17 bond cleavage reaction (Scheme 1, equation (3)) to investigate the Beckett–Casy model.35

5-2. Synthesis of 16,17-seco-Naltrexone Derivatives and Their Binding Profiles for Opioid Receptor Types
The reduction of the oxazolidinone ring in chloride 18,36 prepared from naltrexone derivative 17 (equation (3) in Scheme 1), with LiAlH4 provided tetrahydrofuran derivative 59. Compound 59 was hydrolyzed and subsequently demethylated with BBr3 to afford 60 (Scheme 12). The preparation of another cyclic compound, dihydropyran derivative 64 commenced with naltrexone methyl ether (32) (Scheme 12). Compound 61 obtained by the C16–N17 cleavage reaction of 32 was reduced with Zn in AcOH to give dihydropyran derivative 62 in 87% yield. The keto group in 62 was protected with the acetal, followed by reduction with LiAlH4 to provide amine 63. Deacetalyzation of 63 with 1 M HCl was followed by subsequent demethylation with BBr3 to afford 64.
The other 16,17-seco-naltrexone derivatives were also synthesized from oxazolidinone 18 (Schemes 13 and 14). After exchange reaction of chloride 18 into iodide 65, the treatment of 65 with t-BuOK gave vinyl derivative 66, whereas the reduction of 65 with Zn in AcOH provided ethyl derivative 67 (Scheme 13). Compounds 66 and 67 were converted into compounds 68 and 69 by basic hydrolysis or into 70 and 71 by reduction with LiAlH4. The objective 16,17-seco-naltrexone derivatives 72–75 were obtained by appropriate deprotections of compounds 68–71 (Scheme 13).
Triazole derivative 77 was prepared by 1,3-dipolar cycloaddition of azide 76 with 2,5-norbornadiene,37 which was derived from chloride 18 (Scheme 14). Triazole 77 was converted into the objective derivative 78 via the methods similar to those shown by Scheme 13.
Table 1 shows the results of the opioid receptor binding assays33b of the synthesized compounds. The

binding affinities of all the compounds for the all opioid receptor types were much weaker than that of naltrexone (8). Especially, compounds 64, 73, and 78 were scarcely bound to any of the three receptor types. Meanwhile, compounds 60, 72, 74, and 75 showed moderate binding affinity. In 64, the dihydropyran ring projecting in front of and to the lower side of the molecule may prevent the molecule from binding to the receptor. The orientation of the triazole ring in 78 in front of and to the lower side of the molecule may provide severe steric hindrance. On the other hand, the tetrahydrofuran ring in 60 sticks out to the upper side of the molecule, which may not severely disturb the binding of the molecule to the receptor. The modest binding affinity of 73 to only the κ receptor may result from less steric hindrance caused by the Et group as compared to triazole in 78. In contrast to the N-Me derivative 73, 75 without the N-Me group showed satisfactory Ki values for all the three receptor types. Probably, the Me group of 73 forces the Et substituent to the lower side of the molecule to increase the steric hindrance. Likewise,

74 lacking the N-Me group showed higher affinity than that of corresponding N-Me derivative 72. The observation that 72 or 74 with vinyl substituents showed stronger binding affinities than did 73 or 75 may stem from the sterically smaller vinyl group compared to the Et group. In naltrexone (8), the C15–C16 ethylene unit forming the D ring appears to just fit into the cavity to result in excellent affinity. These results may support the idea of the existence of a cavity structure as proposed in the Beckett–Casy model. However, it is necessary to examine the binding of the molecules without the C15–C16 bond, the 15-16 nornaltrexone derivatives 79 (Figure 8).

5-3. Synthesis of 15-16 Nornaltrexone Derivatives and Their Binding Profiles for Opioid Receptor Types
With the C16–N17 bond-cleaved compound 18 in hand, removal of the two carbon unit from 18 should provide the objective 15-16 nornaltrexone derivatives 79.38 This goal was achieved by a series of reactions (Scheme 15) including the double carboxylation reaction39 (Scheme 1, equation (4)) as a key reaction.
The synthesis of 15-16 nor-14-OH-naltrexone derivatives 88–91 commenced with compound 20 obtained by the double decarboxylation reaction (Scheme 16). The secondary amino group in 20 was protected by a Cbz group followed by oxidation with mCPBA to give allylic alcohol 80 in 68% yield via epoxide ring opening reaction. Catalytic hydrogenation of 80 provided saturated compound 81. The stereochemistries of compounds 80 and 81 were determined by 2D NMR experiments of their corresponding acetamide derivatives. Secondary amine 81 was converted into tertiary amine 82 by reductive methylation. After the treatment of 82 with α-chloroethyl chloroformate (ACE-Cl),36 the obtained oxazolidinone was reduced with LiAlH4 to afford 83. The acetate 84 obtained by acetylation of 82 was treated with Troc-Cl to provide compound 85 because the cyclopropylmethyl (CPM) group was selectively replaced with the Troc group.36 Deprotection of the Troc group in compound 85 with Zn in AcOH facilitated concomitant migration of Ac group from the 14-OH group to the 17-nitrogen to give acetamide 86 in 97% yield, which was hydrolyzed to provide 87. The acetal of each compound 81–83 and 87 was hydrolyzed, and then demethylated with BBr3 to afford the objective 15-16 nor-14-OH-naltrexone derivatives 88–91, respectively. Similarly, the corresponding 15-16 nor-14-H-naltrexone derivatives 97–100 were also synthesized from 20 as shown by Scheme 17. At first, catalytic hydrogenation of 20 gave saturated compound 92. The stereochemistries of compound 92 were determined by 2D NMR experiments. The conversion of 92 into the objective compounds 97–100 was carried out by the manner similar to that shown by Scheme 16.
Tethered compounds 104 and 105 were synthesized from compound 81 (Scheme 18). Treatment of 81 with chloroacetyl chloride and subsequent reaction with NaH gave the lactam, which was reduced with LiAlH4 to give compound 101. According to the methods mentioned above, N-CPM derivative 101 was converted into N-Me derivative 103. The appropriate deprotections of 101 and 103 provided the objective

tethered derivatives 104 and 105, respectively. Another tethered compound was also prepared as shown by Scheme 19. After acetalization of noroxycodone (106), compound 107 was treated with 2-bromoethanol and subsequently with MsCl to give the mesylate, of which cyclization proceeded in the presence of KI and NaH to afford 108. The appropriate deprotections of 108 gave the objective compound 109.
The binding affinities of the synthesized 15-16 nornaltrexone derivatives to the opioid receptor types were evaluated by the competitive binding assays33b (Table 2). The tertiary amines 90, 91, 99, and 100

showed higher affinities for the µ receptor than did the corresponding secondary amines 88, 89, 97, and 98, respectively, suggesting that the higher electron density on the 17-nitrogen in the tertiary amines favored stronger binding to the opioid receptor than for the secondary amines. Furthermore, the compounds 89, 91, 98, and 100 with the 17-CPM group showed stronger affinities than the corresponding 88, 90, 97, and 99 with the Me group, respectively, which may be due to stronger electron releasing effects by the CPM group.36 However, the binding affinities of the compounds 88–91 and 97–100 were three to 500-fold lower than naltrexone (8). These results seem to support the idea of the existence of the cavity described in the Beckett–Casy model. However, the affinities of 14-OH derivatives 88–91 were stronger than those of 14-H derivatives 97–100. The C9–N17 bond of 15-16 nornaltrexone derivatives 88–91 and 97–100 can freely rotate around the axis, whereas the rotation at that site was prevented in naltrexone (8) by the fixed C16–N17 bond (Figure 9). Moreover, in comparing the structures of 14-OH derivatives 88–91 with 14-H derivatives 97–100, the hydrogen bonds between the 17-nitrogen and the 14-OH groups40 in the 14-OH derivatives 88–91 could restrict the free rotation of the C9–N17 bond (Figure 9). As a result, the formation of the hydrogen bond may decrease the population of those rotamers with hardly any binding to the receptor, leading to an overall increase in binding affinities for the 14-OH derivatives 88–91 as compared to the corresponding 14-H derivatives 97–100. The C9–N17 bond in the tethered compounds 104, 105, and 109 cannot freely rotate due to the ethylene bridge between the 17-

nitrogen and 14-OH group. So, these compounds would be expected to display improved binding affinities. However, contrary to our expectation, compounds 104 and 105 were hardly bound to the opioid receptors at all. Moreover, the other tethered compound 109 bound to the opioid receptor, but its affinity was very weak in spite of the presence of the C15–C16 ethylene unit.
It is difficult to explain these outcomes by only the existence of the cavity and/or by the steric hindrance arising from some rotamers. Therefore, we focused on the ionic interaction between the 17-nitrogen and a receptor site. In general, the ion–ion interaction between the ligand and the receptor is the most important pharmacophore,41 which led us to the alternative hypothesis that the orientation of the lone electron pair on the 17-nitrogen may play an important role when a ligand interacts with the opioid receptor. Figure 9 illustrates the orientations of the lone electron pairs in compounds 8, 88–91, 97–100, 104, 105, and 109. In naltrexone (8), both the C15–C16 bond in the D-ring and the hydrogen bonding between 17-nitrogen and the 14-OH group can tightly lock the orientation of the lone electron pair on the17-nitrogen in the axial orientation. Therefore, its affinity for the opioid receptor would be strongest. The hydrogen bond

between the 17-nitrogen and 14-OH group in 88–91 would tend to direct the lone electron pairs in an axial direction in clear contrast to the compounds 97–100 which lack the 14-OH group. In summary, the difference of orientational tendency would influence the binding affinities: 14-OH derivatives 88–91 showed higher affinities than the corresponding 14-H derivatives 97–100. The lone electron pair of tethered compound 109 would be restricted to the equatorial position by an ethylene bridge. As a result, 109 would show weaker affinity than 14-OH derivatives 88–91, which have the lone electron pair located in the axial position, despite the fact that the compound 109 has the C15–C16 ethylene moiety. On the other hand, the lone electron pairs in compounds 104 and 105, which exhibited almost no binding affinities, were predicted to protrude in front of the plane consisting of the 17-nitrogen and the phenol ring. The above discussion would argue against a role for the cavity of the Beckett–Casy model and support the idea the the C15–C16 bond in the D-ring may play a role in fixing the lone electron pair on the 17-nitrogen in the desired axial orientation. However, the possibility cannot be ruled out that a steric hindrance arising from the ethylene moiety in tethered compounds 104, 105, and 109 may decrease the binding abilities of these compounds. The confirmation of our hypothesis requires compounds without steric hindrance, whose lone electron pairs either do or do not project toward the desired axial orientation.

5-4. Synthesis of Naltrexone Derivatives with Contracted or Expanded D-Rings and Their Binding Profiles for Opioid Receptor Types
We designed naltrexone derivatives 110 and 111 with contracted and expanded D-rings to confirm our hypothesis: the desired axial orientation of the lone electron pair on the 17-nitrogen is important for binding to the opioid receptor. Although both compounds would have lone electron pairs with the axial orientation, they would project in opposite direction from each other (Figure 10).42
Synthesis of naltrexone derivative 110 with contracted D-ring commenced with compound 66 (Scheme 20). Ozonolysis of compound 66 and subsequent reduction with NaBH4, followed by hydrolysis provided compound 112. The hydroxy group was converted into the chloride by the Appel43 reaction and the cyclization reaction concomitantly proseeded to give the compound 113 with a contracted D-ring. The

appropriate deprotections of 113 afforded the objective compound 110. On the other hand, the expansion of the D-ring was achieved by one step reaction in 64% yield via halogen–lithium exchange reaction of iodide 65 with t-BuLi (Scheme 21). The amide moiety of the obtained compound 114 with an expanded D-ring was reduced with LiAlH4 to give compound 115. The objective compound 111 was obtained by the consequtive deprotections of 115.
Compound 111 with an expanded D-ring bound to the µ receptor with affinity (Ki (µ) = 0.41 nM, Ki (κ) = 0.373 nM, Ki (δ) = 44.2 nM) comparable to naltrexone (8) (Ki (µ) = 0.335 nM, Ki (κ) = 2.09 nM, Ki (δ) =10.35 nM), whereas compound 110 with a contracted D-ring showed almost no binding affinities for any of the opioid receptors (Ki > 1,000 nM).33b
Morphinan 116 and benzomorphan derivatives 117 with a contracted D-ring and benzomorphan dervative 118 with an expanded D-ring were synthesized in racemic form and their antinociceptive effects were evaluated.44 Compound 116 showed neither agonistic nor antagonistic activities,45a,b while compound 117, which lacked the C-ring, exhibited a 36-fold weaker analgesic effect than morphine.44c The antinociceptive effect of compound 118 was as potent as morphine.44d According to the X-ray

crystallographic analyses of these compounds, all the compounds possessed the lone electron pair on the 17-nitrogen in the axial position orienting toward the same side as the phenol ring. However, Itai and co-workers made an interesting mention about the conformation of compound 118: although the X-ray crystallographic analysis showed that the D-ring46 of 118 was in the quasi-chair conformation and that the lone electron pair projected toward the same side as the phenol ring, the D-ring could flip to adopt the alternative quasi-chair form 118' in which the lone electron pair would take on the axial position orienting toward the opposite site to the phenol ring45c,d (Figure 11). This proposed flip of the D-ring can explain the strong analgesic activity of 118: because the seven-membered ring in 118 is so flexible, it could easily adopt another quasi-chair form 118' having its lone electron pair in the axial direction, i.e., at the site opposite to the phenol ring, and thus the conformer 118' would bind to the opioid recptor to produce a strong antinociception. A comparison of the structures between 116 and 117 reveals that the structure of 116 may be particularly rigid due to an additional ring, the C-ring, that would permit it to adopt only the conformation exhibited by X-ray analysis. As a result, compound 116 would show no opioid activities. On the other hand, the lack of an additional ring in compound 117 would make this compound somewhat more flexible, allowing the D-ring of 117 to flip to alternative conformation 117' with axial lone electron pair protruding toward the opposite site to the phenol ring. The weak analgesic effect induced by 117 may result from the alternative conformer 117'. These experimental results and discussions are consistent with our working hypothesis: the desired axial orientation of the lone electron pair on the 17-nitrogen plays an important role in the ligand’s binding ability to the opioid receptor.
We further investigated the conformations of compounds 110 and 111 by both the conformational analyses using the Conformational Analyzer with Molecular Dynamics And Sampling (CAMDAS) 2.1 program47 and by NOE experiments in D2O. These analyses and experiments also support our working hypothesis. These results, taken together, permit us to conclude that the axial orientation of the lone electron pair on the 17-nitrogen would provide sufficient binding abilities to the opioid receptor and that
the C15–C16 ethylene moiety in the morphine structure would contribute to fixation of this lone electron pair in the optimum axial direction. Thus, effective binding of these compounds with the opioid receptor would be mediated primarily by the axial orientation of the lone electron pair on 17-nitrogen rather than via interaction with the putative cavity in the Beckett–Casy model. Although the interaction between 17-nitrogen and the opioid receptor was generally believed to be a non-directional ionic interaction, the directional property was supported by our conclusion. Therefore, the interaction would be the directionally enforced ionic interaction which was reinforced by the directional hydrogen bond.48,49

6. SYNTHESIS OF TRIPLET DRUGS WITH 1,3,5-TRIOXAZATRIQUINANE SKELETONS AND THEIR PHARMACOLOGIES
Twin drugs, which possess two pharmacophore units in a single molecule, have been described in numerous domains of medicinal chemistry. Symmetrical twin drugs can simultaneously interact with the symmetrical binding sites of a protein to induce increased activity. In contrast, nonsymmetrical twin drugs bind to the individual relevant binding sites to provide dual action.50 Another application of symmetrical or nonsymmetrical twin drugs is tools for investigation of G-protein-coupled receptor (GPCR) dimers/oligomers phenomena.51 However, twin drugs can only play one role, either to increase activity or to provide dual action. Moreover, twin drugs can be applied to only investigations of the GPCR dimers. Triplet drugs with three pharmacophore units could open the door for more versatile investigations. Nonsymmetrical triplet drugs having two identical moieties and one different part could exhibit both increased pharmacological action and dual action. Two of the same moieties may bind the same receptor sites simultaneously while the third part may interact with a different receptor or enzyme. Moreover, triplet drugs would enable us to investigate GPCR oligomers. We have reported the synthesis of novel triplet 25 with 1,3,5-trioxazatriquinane skeleton from α-hydroxyaldehydes (Scheme 1, equation (6)), which could be derived from ketones.30c In this reaction, nitrogen plays an important role in the construction of the novel skeleton. As nitrogen serves as the central atom to gather three identical or nonidentical ketones to form a 1,3,5-trioxazatriquinane skeleton, it acts in a manner analogous to a three-pronged clamp; we termed this phenomenon a "nitrogen clamp" (Scheme 22). To investigate SAR of triplet drugs with morphinan units, we synthesized various triplets including symmetrical and nonsymmetrical triplets, and a capped homotriplet. A symmetrical or nonsymmetrical triplet is composed of three identical or different pharmacophores, respectively, whereas a capped homotriplet has two identical pharmacophore units and an epoxymethano group (cap structure) (Figure 12).

6-1. New Synthetic Method of the Key Intermediate α-Hydroxyaldehyde
The reported synthesis of a triplet is shown in Scheme 23. The method includes nucleophilic addition of lithiated dithiane to the ketone 119 and subsequent acetal exchange reaction and hydrolysis. In this

synthesis, the preparation of the key intermediate α-hydroxyaldehyde 122 requires the use of air- and moisture-sensitive n-BuLi and malodorous 1,3-dithiane. Moreover, the reaction must be carried out at low reaction temperature (-78 ºC). Therefore, we sought reaction conditions that were more practical and concise to develop a new synthetic method using p-toluenesulfonylmethyl isocyanide (Tos-MIC).52 The treatment of ketone 125 with TosMIC at rt in the presence of K2CO3 gave tosyloxazoline intermediate 126, followed by hydrolysis of 126 with 2 M HCl to provide a mixture of a α-hydroxyaldehyde 127 and hemiacetal dimer 128. The reaction of the resulting mixture with NH4Cl in MeOH in the presence of AcONa gave the intermediate oxazoline dimers 129 in 64% from 125 (Scheme 24). Thus, the new method improved the yield of the intermediate oxazolidine dimer 129.

6-2. Synthesis of Symmetrical and Nonsymmetrical Triplet Drugs with Morphinan Skeletons and Their Pharmacologies
According to the method indicated by Scheme 23 (previous method), oxycodone (119), naltrexone methyl ether (32), and 14-dehydroxynaltrexone methyl ether (130) were converted into the corresponding symmetrical triplets 124, 131, and 132, which were treated with BBr3 to give the respective phenolic hydroxy derivatives 133–135 (Scheme 25).53
It is noteworthy that an oxazoline dimer like 123 (Scheme 23) could be isolated, because the oxazoline dimer enabled the effective synthesis of nonsymmetrical triplets. The example of synthesizing triplet 137 with two N-CPM and one N-Me substituents is shown in Scheme 26. The oxazoline dimer 136 with the N-CPM groups was treated with α-hydroxyaldehyde 122 with the N-Me group in the presence of

camphorsulfonic acid (CSA) to provide nonsymmetrical triplet 137 in 50% yield. By the same manner, another nonsymmetrical triplet 138 was also prepared. The obtained nonsymmetrical triplets 137 and 138 were demethylated with BBr3 to give the corresponding phenolic hydroxy derivatives 139 and 140 (Scheme 26).
The binding affinities of the synthesized triplet drugs for the opioid receptor types were shown in Table 3.33b The symmetrical triplet 133 with three N-Me groups bound most strongly to the µ receptor among the three types. Although its Ki value for the µ receptor was larger than that of naltrexone (8), the selectivity of 133 for the µ receptor over the κ receptor was higher than that of naltrexone (8). With an increase in the number of N-CPM groups, the selectivity for the κ receptor increased; the order of increasing κ selectivity was 133 < 140 < 139 < 134. These results were in good agreement with reports that the N-Me group contributed to the µ selectivity, while the N-CPM group favored the κ selectivity.2b,54 The 14-dehydroxy symmetrical triplet 135 with three N-CPM groups had lower affinity for the κ receptor than the corresponding 14-OH triplet 134, which was consistent with our previous reports.2b
Subcutaneous administration of 133, which showed the highest selectivity and affinity for the µ receptor,

induced dose-dependent antinociceptive effects in the acetic acid writhing test.2b This effect could be antagonized with the µ antagonist naloxone (Figure 13). The antinociception of 133 (ED50 = 0.034 µmol/kg) was 56-fold higher than that of morphine (ED50 = 1.9 µmol/kg).55 The strong activity of 133 might result from its simultaneous occupancy of three µ opioid receptors. It is noteworthy that 133 did show profound analgesic effects despite its lacking drug-like properties as a central nervous system drug, e.g., an extremely large molecular weight (MW = 957) and numerous nitrogen and oxygen atoms (the sum of the nitrogen and oxygen atoms in 133 is over six).56 It is not clear why a triplet drug with these

properties showed strong antinociception, but certain transporters may help the absorption and/or penetration of the triplet into the brain.

6-3. Synthesis of Capped Homotriplet Drugs with Morphinan Skeletons and Their Pharmacologies
To compare with pharmacological effects induced by triplet drugs, capped triplets, which have two pharmacophore units and the epoxymethano structure (cap structure), would serve as useful reference compounds (Figure 12). We expected the capped triplet to be a useful tool to investigate the phenomenon of GPCR dimerization. Therefore, we attempted to synthesize capped homotriplet 141 using a new method (Scheme 27).52 Other capped triplets 143–147 (Scheme 29) were synthesized from the corresponding ketones by the same manner. In the reaction shown by Scheme 27, the kinetically controlled oxazoline dimer 136R with R-configuration at the *-position (Scheme 28) was reported to be epimerized into the thermodynamically controlled oxazoline dimer 136S with S-configuration during the reaction to provide the 1,3,5-trioxazatriquinone skeleton structure with S-configuration at all methyne positions.30c It is intersting that the isolated R-oxazoline dimer 136R with TMSOTf instead of CSA afforded capped homotriplet 142 with R-configuration at all methyne positions (#-positions) (Scheme 28). The configurations of the 1,3,5-trioxazatriquinane skeleton moieties in capped homotriplets 141 and 142 were determined by 2D-NMR experiments. Thus obtained capped homotriplets 141–14757 and oxazoline dimers 136R and 136S were demethylated to give phenolic hydroxy derivatives 148–156 (Scheme 29).
The binding affinities of the synthesized capped homotriplets and oxazoline dimers for the opioid receptor types are shown in Table 4.33a Capped homotriplets 150 and 154 bound to the opioid receptors, but their affinities were much lower compared to the other test compounds. Both the weak electron donating ability and steric hindrance of N-i-Bu groups in 150 may disturb its binding to the opioid receptors. Even though the Me group is a weaker electron donor than the i-Bu group, the affinities of 149 with N-Me groups were higher than those of 150. These results may stem from low steric hindrance of the Me group in comparison to the i-Bu group. Contrary to the low affinity of 154, its stereoisomer 148 showed sufficient affinity for the opioid receptor types. The difference of affinities between the two

stereoisomers may be due to the different configurations of the trioxazatriquinane skeletons in the two isomers. The absence of the 4,5-epoxy bridge (compound 152) or the angular OH group (compound 153) had almost no influence on their affinities. Interestingly, the capped homotriplet 148 showed µ selectivity, whereas its precursor, the oxazoline dimer 156, exhibited κ selectivity. The superimposition of 148 or 156 onto the selective κ antagonist nor-BNI provided a clue to explain the difference of the receptor type selectivities between 148 and 156. The two 4,5-epoxymorphinan units in 156 occupied a relative spatial location similar to that of nor-BNI, while the same units of 148 were located in a different position (Figure 14). To the best of our knowledge, 149 showed the highest selectivity for the µ receptor over the κ receptor among any of the reported non-peptidic ligands.58 Therefore, 149 is expected to be a useful tool for the investigation of pharmacologies via the µ receptor.
Capped homotriplet 149 dose-dependently produced antinociception in the acetic acid writhing test 2b (Figure 15 (A)) and its effect was significantly reduced by the µ antagonist naloxone (Figure 15 (B)). The

potency of the analgesic effect induced by 149 (ED50 = 0.18 µmol/kg) was 11-fold more potent than that of morphine (ED50 = 1.9 µmol/kg), but about five fold less potent than that of symmetrical triplet 133 (ED50 = 0.034 µmol/kg).53 It is interesting that the increment of morphinan units exerted non-linearly increasing effects of antinociception. These phenomena would result from the features of symmetrical twin and triplet drugs mentioned above.

7. SYNTHESIS OF PROPELLANE DERIVATIVES WITH AFFINITIES FOR OPIOID RECEPTORS
The receptor type selectivity is generally influenced by the 17-substituents; 17-Me and 17-CPM derivatives tend to bind preferably to the µ and the κ receptors, respectively. Indeed, morphine and oxymorphone (157) with the 17-Me group showed high selectivity for the µ receptor, whereas naltrexone (8) with the 17-CPM substituent bound to the κ receptor with a smaller Ki value than did oxymorphone, the corresponding derivative with a 17-Me group (157) (Figure 16). A similar tendency was observed in the selective κ agonist, nalfurafine (1, Figure 1) and the selective κ antagonist, nor-BNI, which have 17-CPM substituents; the conversion of the 17-substituent from CPM into a Me group in nalfurafine (1) significantly lowered the κ selectivity,2b,2e whereas the 17-Me derivative of nor-BNI showed full agonistic

activity for the µ receptor.60
Taking into account the tendencies mentioned above, a careful observation of the relationship between receptor type selectivities and the presence or absence of the 4,5-epoxy ring in the compounds depicted in Figure 16 provided an interesting correlation: The morphinan derivatives 8 and 158 with a 4,5-epoxy ring

showed rather lower κ selectivity (µ/κ) despite having 17-CPM groups, while the derivatives 159–161 without the 4,5-epoxy ring tended to show higher κ selectivity (Figure 16).58e The benzomorphan derivatives like (–)-pentazocine and (–)-bremazocine, which showed κ selectivity, also have no 4,5-epoxy ring. This tendency led us to propose that, with respect to the 17-CPM derivatives, the position of the plane composed of the A and B rings, which can be defined by the torsion angle C11–C12–C13–C14, would influence the receptor type selectivity and that a decrease in the torsion angle could improve the κ

selectivity. The torsion angles C11–C12–C13–C14 in 4,5-epoxymorphinans are approximately 30º (Figure 17(A)) and are fixed by both the 4,5-epoxy ring and the 10-methylene bridge. These compounds like 8 and 158 prefer to bind the µ receptor. On the other hand, in morphinan derivatives lacking the 4,5-epoxy ring or in the benzomorphans, the torsion angle C11–C12–C13–C14 could be less than 30º (Figure 17(B)) because the plane comprised of the A and B rings was not fixed as tightly, permitting rotation around the C12–C13 axis. These compounds tend to show κ selectivity. This working hypothesis led us to the propellane derivatives 162a whose A and B rings are fixed and the torsion angle C11–C12–C13–C1461 is about 0º (Figure 17(C)). The structure in the solid state of propellane derivative 162b (Scheme 30), which was prepared from the extremely stable iminium ion 23 (Scheme 1, equation (5')), was confirmed by X-ray crystallographic analysis.62
Additionally, Carroll and colleagues recently reported that N-substituted cis-4a-(3-hydroxyphenyl)-8a-methyloctahydroisoquinolines 163 was an opioid antagonist.63a According to Carroll et al., JDTic (164)63b or MTHQ (165),63c which were κ antagonists belonging to this chemical class, had the 3-hydroxyphenyl group in the equatorial position and a trans-3,4-dimethyl structure, and these structural features would play an essential role in antagonist activity regardless of the nitrogen substituents (Figure 18). From this point of view, the propellane derivatives 162 have two structural features: an axial alkylene group corresponding to the axial 3-Me group in 163 and the 3-hydroxyphenyl group fixed in the axial conformation by a methylene bridge (Figure 18). Therefore, the propellane derivatives 162 were very interesting compounds from two viewpoints: 1) the decrease in torsion angles C11–C12–C13–C14 would improve the κ selectivity and 2) the validation of Carroll's proposal that both the equatorial 3- hydroxyphenyl conformation and the trans-3,4-dimethyl structure in the series of derivatives of 163 would exert the antagonist activity.54
For the synthesis of objective propellane derivatives 162 (Scheme 30), the extremely stable iminium 23 (Scheme 1, equation (5')) was reduced with NaBH4 to give the saturated propellane 166a. After exchange of N-CPM substituent into the N-Troc group, the reduction of the obtained carbamate 167 with LiAlH4

provided N-Me derivative 166b. N-((1-Hydroxycyclopropyl)methyl) derivative 166c was prepared by the treatment of compound 168 with EtMgBr in the presence of Ti(Oi-Pr)4 (Kulinkovich reaction)64 in 52% yield. Compound 168 was obtained from carbamate 167 by deprotection of the Troc group and subsequent alkylation. Thus prepared propellane derivatives 166 were appropriately deprotected to afford the objective phenolic hydroxy derivatives 162.
Table 5 exhibited the binding affinities of prepared propellanes 162 (Table 5).33b Both 162a with the N-CPM group and 162c with the N-((1-hydroxycyclopropyl)methyl) substituent displayed high selectivity for the κ receptor. Their selectivities for the κ receptor over the µ receptor (162a: µ/κ= 3.3, 162c: µ/κ = 3.6) were higher than those of the representative κ agonist nalfurafine (µ/κ = 2.5) and (–)-pentazocine (µ/κ = 1.3). These results support our conjecture that a decrease in the torsion angle C11–C12–C13–C14 in morphinan-related derivatives with the N-CPM substituent would improve the κ selectivity. Propellane derivatives 162a and 162c displayed lower binding affinities for all receptor types than did nalfurafine (1) and (–)-pentazocine. This result may be due to the cis-fused C and D rings. Contrary to the trans-fused decahydroisoquinoline derivatives, the cis-fused derivatives showed very weak analgesic effects.66 In contrast to 162a and 162c, 162b with an N-Me group showed high binding affinity for the µ receptor, but

its affinity for the κ receptor decreased. This result was consistent with the feature of N-Me derivatives mentioned above, i.e., preference for the µ receptor.
N-CPM-Derivative 162a produced antinociceptive effects in the mouse acetic acid writhing test.2b The analgesic effect by 162a was as potent as that by morphine (ED50 = 0.86 mg/kg, s.c.). The antinociception of 162a was mainly antagonized by κ antagonist nor-BNI and partly by µ antagonist naloxone (Figure 19). This result indicates that 162a was a somewhat selective κ agonist and is also consistent with our working hypothesis. Moreover, the result suggests that the elicitation of antagonist activity requires the equatorial 3-hydroxy group, not the axial methyl (alkylene) group.
The 6-keto group in the C-ring of propellane 162a could exist in a more elevated position compared to the 6-keto group in naltrexone (8). Therefore, the introduction of an amide side chain at the 6- or 7-position61 would be more effective for improving the κ selectivity because the amide side chain introduced into the propellane skeleton would be expected to locate in a position similar to that of the amide side chain in the active conformation of nalfurafine (1)2c,d,f (Figure 20). Therefore, we next synthesized propellane derivatives with an amide side chain in the 6- or 7-position to improve the κ selectivity.67
The propellane derivatives 175 and 176 with a 6-amide side chain were prepared from 166a (Scheme 31). After reductive amination of 166a with benzylmethylamine, hydrogenolysis of the obtained tertiary amines 169 and 170 gave secondary amines 171 and 172, respectively. Amines 171 and 172 were acylated with the corresponding acyl chlorides, followed by O-demethylation to afford the respective propellane derivatives 175 and 176.
The preparation of propellane derivatives 185 and 186 with a 7-amide side chain also commenced with 166a (Scheme 32). The methoxycarbonyl group was introduced at the 7-position by the reaction of 166a with CO(OMe)2 in the presence of NaH. The obtained β-ketoesters 178 and 179 were converted into α,β-

unsaturated ester 180 by the reduction with NaBH4 and subsequent dehydration with POCl3. The hydrogenation of 180 provided saturated 7-esters 181 (α-isomer) and 182 (β-isomer) in 5% and 77% yield, respectively. The attempted epimerization of major product 182 with LDA gave α-isomer 181 in 24% yield with recovery of 182 in 65%. The alternative synthesis of 7-esters 181 and 182 was carried out by reduction of 180 with Mg68 in respective yield of 30% and 53%. The obtained esters 181 and 182 were converted into the respective 7-amides 183 and 184 by the ester–amide exchange reaction with the appropriate lithium amide. The objective propellane derivatives 185 and 186 were obtained by the O-demethylation of 183 and 184, respectively.

The propellane derivatives 188 with the α,β-unsaturated amide moiety were derived from α,β-unsaturated ester 180 by the ester–amide exchange reaction and subsequent O-demethylation (Scheme 33).
The binding affinities of the synthesized propellane derivatives for the opioid receptors are shown in Table 6. All the 6-amide derivatives 175 and 176 bound to all three receptor types with smaller Ki values than propellane 162a lacking the amide side chain. Compound 176b showed improved κ selectivity over the µ receptor compared to nalfurafine (1) and propellane 162a. Interestingly, 6β-isomers 176 were more κ selective over the µ receptor than the corresponding 6α-isomers 175. This result may be caused by the orientation of the 6β-amide side chain toward the upper side of the C-ring. Meanwhile, the 7-amide derivatives 185, 186, and 188 showed lower affinities than the 6-amide derivatives 175 and 176. Especially, the affinities of 7β-isomers 186 were low and 186b hardly bound to the δ and κ receptors. On the other hand, 7α-isomers 185 and α,β-unsaturated amides 188 interacted with the three receptor types with somewhat higher affinities compared to the β-isomers 186. The α,β-unsaturated amides 188 showed µ selectivity, whereas the α-isomers 185 except for 185c exhibited κ selectivity. The κ selectivities of 185a and 185b were higher than those of nalfurafine (1) and 6β-amide 176b. The different orientation of the amide side chain may provide these outcomes (Figure 21). The amide side chain of 185 may be able to locate in a direction that enhances binding to the κ receptor, whereas that of 188 cannot. However, it is difficult to explain the extreme decrease in the affinities of the 7β-isomer 186 by an unfavorable orientation of the amide side chain, i.e., the side chain is incapable of functioning as the κ address. Therefore, we postulated that the flexible 7β-side chain could locate over the 17-nitrogen to interfere with the ionic interaction between the 17-nitrogen and the opioid receptor. The ionic interaction of the 17-nitrogen is one of the three important interactions between ligand and opioid receptor: the other two interactions are a π–π interaction with the phenol ring and a hydrogen bond with the phenolic hydroxy group. Figure 22 depicts the results of conformational analyses of three 7-amides 185b, 186b, and 188b using CAMDAS 2.1 program.47 The benzene ring of the 7β-amide side chain in 186b located over the 17-nitrogen and almost completely shields the lone electron pair of the 17-nitrogen (Figure 22 (C)). On the other hand, the side chain in 7α-amide 185b would not shield the lone electron pair of 17-nitrogen (Figure 22 (A)). The shielding effect of the side chain in the α,β-unsaturated amide 188b would be insufficient (Figure 22 (B)). The results of conformational analyses supported our hypothesis and indicated that the ionic interaction between the 17-nitrogen and the opioid receptor would be especially important among the three known ligand–receptor interactions in opioid action.34a,69

8. CONCLUDING REMARKS
In this review, we have described the recent progress of our investigations, including interesting reactions using naltrexone derivatives and the pharmacological properties of the synthesized derivatives. A key reaction in the (–)-homogalanthamine synthesis was the Grob fragmentation, in which the observed stereoelectronic effect due to characteristic structure of naltrexone (8) was utilized. Novel derivatives with oxazatricyclodecane or propellane skeletons would be useful as lead compounds for novel opioid ligands exhibiting receptor type selectivities. The investigation of the Beckett–Casy model suggested that the interaction between the 17-nitrogen and the opioid receptor would be not a simple ionic but an enforced ionic interaction with directional properties. Triplet drugs have promising features. Symmetrical triplets with 17-Me groups described in this review showed increased agonistic activities. Nonsymmetrical triplet drugs would exhibit dual or triple pharmacological actions. Moreover, these triplets are expected to be useful tools for investigating the phenomena of GPCR dimerization and/or oligomerization. We are now vigorously pursuing the synthesis of new derivatives and the utilization of the obtained derivatives.

ACKNOWLEDGMENTS
We acknowledge the Institute of Instrumental Analysis of Kitasato University, School of Pharmacy for its facilities. We also acknowledge the financial support from Grant-in-Aid for Scientific Research and the Uehara Memorial Foundation and the Shorai Foundation for Science and Technology.

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