Adenosine Agonists. Characterization of the N₆-Subregion of the Adenosine A₂ Receptor via Molecular Modeling Techniques

Abstract

Biological effects of adenosine are mediated by extracellular adenosine receptors that are divided into two main subtypes, A₁ and A₂, which inhibit and stimulate, respectively, adenylate cyclase (Van Calker et al., 1979; Londos et al., 1980). A₂ receptors have been further subdivided into A_2a and A_2b forms, based on their high (10⁻⁷ M) and low (10⁻⁵ M) affinities for adenosine. Highly selective ligands such as R-PLA (Vapaatalo et al., 1975) and CHA (Moos et al., 1985) are known for the A₁ receptor; however, only weak, 5-fold selective (CV-1808) or nonselective (NECA) ligands are known for the A_2a receptor (Kawazoe et al., 1980; Prasad et al., 1980). Previous research (Heffner et al., 1985) demonstrated that A_2a-selective compounds such as CV-1808 had a desirable antipsychotic profile in secondary pharmacological tests such as sidman avoidance. It was hoped that a potent, highly selective A_2a agonist would enhance these antipsychotic effects and lead to a clinically useful drug.