Purine Receptors: GPCR Structure and Agonist Design

Selective enhancement of the amine-bearing neoligand MRS 3366. The human A_2A AR is strategically mutated [T88D (3.36)] to provide an acidic side chain for electrostatic complementarity (A) to an amine-functionalized adenosine derivative MRS 3366 (12). Placement of the amine group closer to the ribose moiety in 5′-amino-5′-deoxyadenosine (B) fails to result in an enhancement. The receptors were expressed in COS-7 cells. In the radioligand binding competition curves shown, the squares represent wild-type, and the triangles T88D mutant receptors. [³H]ZM241385 is a potent antagonist radioligand of the A_2A AR. [The color range of the electrostatic potential Connolly surface calculated using the MOLCAD module of SYBYL^® is displayed from red (most positive) to blue (most negative). The nucleoside is represented by ball-and-stick model with atom-type-color. The hA_2A T88D neoceptor is displayed as a tube model using the MOLCAD ribbon surface. A portion of EL2 is visable at the top of the figure.]