A-412997 is a selective dopamine D 4 receptor agonist in rats

Abstract

A-412997 (2-(3′,4′,5′,6′-tetrahydro-2′ H-[2,4′] bipyridinyl-1′-yl)- N- m-tolyl-acetamide) is a highly selective dopamine D 4 receptor agonist that binds with high affinity to rat dopamine D 4 and human dopamine D 4.4 receptors ( K i = 12.1 and 7.9 nM, respectively). In contrast to the dopamine D 4 receptor agonists PD168077 and CP226269, A-412997 showed a better selectivity profile and no affinity < 1000 nM for other dopamine receptors or any other proteins in a panel of seventy different receptors and channels. In functional assays using calcium flux, A-412997 was a potent full agonist at rat dopamine D 4 receptors (28.4 nM, intrinsic activity = 0.83) and did not activate rat dopamine D 2L receptors, unlike CP226269. Dopamine D 4 receptor selective agonists have been shown to induce penile erection in rats by central mechanisms. A-412997 induces penile erection in a conscious rat model (effective dose = 0.1 μmol/kg, s.c.) with comparable efficacy as the nonselective D 2-like agonist, apomorphine. When dosed systemically, A-412997 crossed the blood brain barrier rapidly and achieved significantly higher levels than PD168077. A-412997 is a highly selective dopamine D 4 receptor agonist and a useful tool to understand the role of dopamine D 4 receptors in rat models of central nervous system processes and disease.