Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10838371 | Pharmacology Biochemistry and Behavior | 2005 | 8 Pages |
Abstract
A-412997 (2-(3â²,4â²,5â²,6â²-tetrahydro-2â²H-[2,4â²] bipyridinyl-1â²-yl)-N-m-tolyl-acetamide) is a highly selective dopamine D4 receptor agonist that binds with high affinity to rat dopamine D4 and human dopamine D4.4 receptors (Ki = 12.1 and 7.9 nM, respectively). In contrast to the dopamine D4 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 D4 receptors (28.4 nM, intrinsic activity = 0.83) and did not activate rat dopamine D2L receptors, unlike CP226269. Dopamine D4 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 D2-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 D4 receptor agonist and a useful tool to understand the role of dopamine D4 receptors in rat models of central nervous system processes and disease.
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Authors
Robert B. Moreland, Meena Patel, Gin C. Hsieh, Jill M. Wetter, Kennan Marsh, Jorge D. Brioni,