title: A-412997 is a selective dopamine D4 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 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 micromol/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.
authors.affiliation: Neuroscience Research, Global Pharmaceutical Research and Development, AP9A Room 219, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois, 60064-6123, USA. robert.moreland@abbott.com
authors.forename: Robert B
authors.initials: RB
authors.lastname: Moreland
authors.forename: Meena
authors.initials: M
authors.lastname: Patel
authors.forename: Gin C
authors.initials: GC
authors.lastname: Hsieh
authors.forename: Jill M
authors.initials: JM
authors.lastname: Wetter
authors.forename: Kennan
authors.initials: K
authors.lastname: Marsh
authors.forename: Jorge D
authors.initials: JD
authors.lastname: Brioni
mesh_terms: D000081:Acetamides / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D018491:Dopamine Agonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D010410:Penile Erection / Q000187:drug effects; D011725:Pyridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D050638:Receptors, Dopamine D4 / Q000819:agonists*
chemical_list: C506999:2-(3',4',5',6'-tetrahydro-2'H-(2,4') bipyridinyl-1'-yl)-N-m-tolyl-acetamide; D000081:Acetamides; D018491:Dopamine Agonists; D011725:Pyridines; D050638:Receptors, Dopamine D4