A-77636: a potent and selective dopamine D1 receptor agonist with antiparkinsonian activity in marmosets.
A-77636, ((1R,3S) 3-(1'-adamantyl)-1-aminomethyl-3,4-dihydro-5,6-dihydroxy-1H-2-benz opyran hydrochloride), is a selective dopamine D1 receptor agonist. In a battery of receptor binding assays, A-77636 shows the highest affinity (pKi = 7.40 +/- 0.09; Ki = 39.8 nM) for the dopamine D1 receptor. A-77636 is an agonist at the dopamine D1 receptors in the fish retina (pEC50 = 8.13; EC50 = 1.1 nM; intrinsic activity = 102% of dopamine) and the rat caudate-putamen (pEC50 = 8.97; intrinsic activity = 134% of dopamine). The compound is functionally inactive at dopamine D2 receptors (EC50 > 10 microM). In rats with unilateral 6-OHDA (6-hydroxydopamine) lesions of the nigro-striatal dopaminergic pathway, A-77636 elicits prolonged (> 20 h) contralateral turning that is blocked by SCH 23390, a D1 receptor antagonist, but not by haloperidol at doses selective for the dopamine D2 receptor. Higher doses of A-77636 produce forelimb clonus in rats and mice. When tested in marmosets treated with MPTP to induce a parkinsonian-like state, A-77636 increases locomotor activity and decreases the severity of the parkinsonian-like symptoms: the compound is active after either subcutaneous or oral administration. A-77641, the optical antipode of A-77636, has a lower affinity towards the dopamine D1 receptor (pKi = 5.14, Ki = 7200 nM), is less potent as a dopamine D1 receptor agonist (pEC50 = 5.65; EC50 = 2200 nM), fails to elicit turning in the 6-OHDA-lesioned rat, and lacks antiparkinsonian efficacy in the MPTP-treated marmoset.(ABSTRACT TRUNCATED AT 250 WORDS)
Kebabian
J W
JW
Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL 60064.
Britton
D R
DR
DeNinno
M P
MP
Perner
R
R
Smith
L
L
Jenner
P
P
Schoenleber
R
R
Williams
M
M
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000218:Adamantane / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D001552:Benzazepines / Q000494:pharmacology; D001578:Benzopyrans / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D002144:Callithrix; D002460:Cell Line; D015259:Dopamine Agents / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D005399:Fishes; D007279:Injections, Subcutaneous; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D016627:Oxidopamine / Q000494:pharmacology; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy*; D051381:Rats; D017447:Receptors, Dopamine D1 / Q000187:drug effects / Q000378:metabolism*
D000978:Antiparkinson Agents; D001552:Benzazepines; D001578:Benzopyrans; D015259:Dopamine Agents; D017447:Receptors, Dopamine D1; C079415:A 77636; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D016627:Oxidopamine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000218:Adamantane