title: ABT-431: the diacetyl prodrug of A-86929, a potent and selective dopamine D1 receptor agonist: in vitro characterization and effects in animal models of Parkinson's disease.
abstract: (-)-Trans 9,10-hydroxy-2-propyl-4,5,5a,6,7,11b-hexahydro-3-thia-5- azacyclopent-1-ena[c]phenanthrene hydrochloride (A-86929) is a potent and selective full agonist at the dopamine (DA) D1-like receptor. Judging by its binding affinities to the D1 and D2 classes of receptors, the compound is approximately 20-fold D1 receptor-selective, whereas relative potencies based on functional in vitro assays indicate that A-86929 is greater than 400-fold D1-selective. A-86929 has moderate to weak (Ki > 1 microM) affinity at other monoaminergic and peptidergic receptors, at ion channels and at monoamine uptake sites. The catechol of A-86929 was bis-acetylated to produce the prodrug, (-)-trans 9,10-acetoxy-2-propyl-4,5,5a,6,7,11-b-hexahydro-3-thia- 5-azacyclopent-1-ena[c]phenanthrene hydrochloride (ABT-431), which is more chemically stable yet is rapidly converted to the parent compound with a half-life of less than 1 min in plasma. Both A-86929 and ABT-431 produced contralateral rotation in rats bearing unilateral 6-hydroxydopamine lesions, with ED50 values of 0.24 mumol/kg s.c. and 0.54 mumol/kg s.c., respectively. A-86929 and ABT-431 improved behavioral disability scores and increased locomotor activity in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned marmoset model of Parkinson's disease in a dose-dependent manner (the minimum effective dose was 0.10 mumol/kg s.c.). When administered three times daily for 30 consecutive days to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned marmosets, A-86929 significantly improved disability scores throughout the duration of the study. Current Parkinson's disease therapy includes L-dopa, which stimulates both classes of DA receptors by virtue of its conversion to DA in vivo, and direct-acting D2-selective agonists. Stimulation of the D2 receptor, which is associated with all current DA agonist-based therapies, may contribute to their dose-limiting side effects. An agent such as A-86929 (or its prodrug ABT-431), which selectively stimulates the D1 receptor, may represent a novel mechanism for Parkinson's disease therapy with the potential for an improved side-effect profile and, consequently, improved patient compliance.
authors.affiliation: Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois, USA.
authors.forename: K
authors.initials: K
authors.lastname: Shiosaki
authors.forename: P
authors.initials: P
authors.lastname: Jenner
authors.forename: K E
authors.initials: KE
authors.lastname: Asin
authors.forename: D R
authors.initials: DR
authors.lastname: Britton
authors.forename: C W
authors.initials: CW
authors.lastname: Lin
authors.forename: M
authors.initials: M
authors.lastname: Michaelides
authors.forename: L
authors.initials: L
authors.lastname: Smith
authors.forename: B
authors.initials: B
authors.lastname: Bianchi
authors.forename: S
authors.initials: S
authors.lastname: Didomenico
authors.forename: L
authors.initials: L
authors.lastname: Hodges
authors.forename: Y
authors.initials: Y
authors.lastname: Hong
authors.forename: L
authors.initials: L
authors.lastname: Mahan
authors.forename: J
authors.initials: J
authors.lastname: Mikusa
authors.forename: T
authors.initials: T
authors.lastname: Miller
authors.forename: A
authors.initials: A
authors.lastname: Nikkel
authors.forename: M
authors.initials: M
authors.lastname: Stashko
authors.forename: D
authors.initials: D
authors.lastname: Witte
authors.forename: M
authors.initials: M
authors.lastname: Williams
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D000978:Antiparkinson Agents / Q000378:metabolism / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D016466:CHO Cells; D002144:Callithrix; D003342:Corpus Striatum / Q000378:metabolism / Q000648:ultrastructure; D006224:Cricetinae; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005399:Fishes; D006801:Humans; D007700:Kinetics; D008297:Male; D051379:Mice; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology*; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology*; D015363:Quinolones; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000819:agonists* / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000378:metabolism / Q000494:pharmacology*; D013876:Thiophenes
chemical_list: D000978:Antiparkinson Agents; D018491:Dopamine Agonists; D011355:Prodrugs; D011725:Pyridines; D015363:Quinolones; D017447:Receptors, Dopamine D1; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; C095428:adrogolide hydrochloride; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C095427:A 86929