title: A-69024: a non-benzazepine antagonist with selectivity for the dopamine D-1 receptor.
abstract: A-69024 HBr, 1-(2-bromo-4,5-dimethoxybenzyl)-7-hydroxy-6-methoxy-2-methyl-1,2,3,4- tetrahydroisoquinoline hydrobromide, is a selective antagonist of the dopamine D-1 receptor. A-69024 HBr shows an apparent affinity toward the D-1 receptor (identified using [125I]SCH 23390) of 12.6 (4.15-38.3) nM (mean (90% CL), n = 3); the apparent affinity toward the D-2 receptor (identified using [3H]spiroperidol is 1 290 (1,200-1,380) nM (n = 3); using [125I]lysergic acid diethylamine to identify the 5-HT1C receptor gives apparent affinity of 17,800 (9,700-32,600) nM (n = 3). In assays of adenylate cyclase activity, A-69024 HBr antagonizes the D-1 receptor with a calculated affinity of 43.9 (17.5-110) nM (n = 5), while the molecule antagonizes the D-2 receptor with a calculated affinity greater than 400 nM. Behavioral studies demonstrate that A-69024 HBr (5 mg/kg s.c.) is able to block both amphetamine-induced locomotor activity and apomorphine-induced stereotypy. Furthermore, A-69024 HBr blocks SF&F 38393-, but not quinpirole-, induced rotation in rats having unilateral 6-hydroxydopamine lesions of the substantia nigra. When administered at behaviorally effective doses. A-69024 HBr neither increases the concentration of serum prolactin nor potentiates dihydroxyphenylalanine (DOPA) accumulation in the caudate-putamen of rats pretreated with the DOPA decarboxylase inhibitor NSD 1015. Because A-69024 is a dopamine receptor antagonist discriminating between the D-1 and D-2 receptors, it may be a useful research tool.
authors.affiliation: Neuroscience Research Division, Department 47U, Abbott Laboratories, Abbott Park, IL 60064.
authors.forename: D J
authors.initials: DJ
authors.lastname: Kerkman
authors.forename: M
authors.initials: M
authors.lastname: Ackerman
authors.forename: L D
authors.initials: LD
authors.lastname: Artman
authors.forename: R G
authors.initials: RG
authors.lastname: MacKenzie
authors.forename: M C
authors.initials: MC
authors.lastname: Johnson
authors.forename: L
authors.initials: L
authors.lastname: Bednarz
authors.forename: W
authors.initials: W
authors.lastname: Montana
authors.forename: K E
authors.initials: KE
authors.lastname: Asin
authors.forename: H
authors.initials: H
authors.lastname: Stampfli
authors.forename: J W
authors.initials: JW
authors.lastname: Kebabian
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001552:Benzazepines / Q000031:analogs & derivatives*; D001667:Binding, Competitive / Q000187:drug effects; D002375:Catalepsy / Q000139:chemically induced; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D006220:Haloperidol / Q000494:pharmacology; D007279:Injections, Subcutaneous; D007457:Iodine Radioisotopes; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010208:Papaverine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D011388:Prolactin / Q000097:blood; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects*; D013239:Stereotyped Behavior / Q000187:drug effects; D044005:Tetrahydroisoquinolines
chemical_list: C049558:8-iodo-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol; D001552:Benzazepines; D007457:Iodine Radioisotopes; D011954:Receptors, Dopamine; D044005:Tetrahydroisoquinolines; C061450:A 69024; D004295:Dihydroxyphenylalanine; D011388:Prolactin; D010208:Papaverine; D000262:Adenylyl Cyclases; D006220:Haloperidol; D001058:Apomorphine