A68930: a potent agonist selective for the dopamine D1 receptor.
A68930, (1R,3S)-1-aminomethyl-5,6-dihydroxy-3-phenylisochroman HCl, is a potent (EC50 = 2.5 nM), partial (intrinsic activity = 66% of dopamine) agonist in the fish retina dopamine-sensitive adenylate cyclase model of the D1 dopamine receptor. In the rat caudate-putamen model of the D1 dopamine receptor, A68930 is a potent (EC50 = 2.1 nM) full agonist. In contrast, A68930 is a much weaker (EC50 = 3920 nM) full agonist in a biochemical model of the dopamine D2 receptor. The orientation of the 3-phenyl substituent in the molecule is critical for the affinity and selectivity of the molecule towards the dopamine D1 receptor. A68930 also displays weak alpha 2-agonist activity but the molecule is virtually inactive at the alpha 1- and beta-adrenoceptors. When tested in rats bearing a unilateral 6-OHDA lesion of the nigro-neostriatal neurons, A68930 elicits prolonged (greater than 20 h) contralateral turning that is antagonized by dopamine D1 receptor selective doses of SCH 23390 but not by D2 receptor selective doses of haloperidol. In this lesioned rat model, A68930 increases 2-deoxyglucose accumulation in the lesioned substantia nigra, pars reticulata. When tested in normal rats, A68930 elicits hyperactivity and, at higher doses, produces a forelimb clonus.
Neuroscience Research Division, Abbott Laboratories, Abbott Park, IL 60064.
M P
MP
DeNinno
R
R
Schoenleber
R
R
MacKenzie
D R
DR
Britton
K E
KE
Asin
C
C
Briggs
J M
JM
Trugman
M
M
Ackerman
L
L
Artman
L
L
Bednarz
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D001665:Binding Sites; D002347:Carps; D002839:Chromans / Q000378:metabolism / Q000494:pharmacology*; D003847:Deoxyglucose / Q000378:metabolism; D015259:Dopamine Agents / Q000378:metabolism / Q000494:pharmacology*; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D016627:Oxidopamine / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000378:metabolism; D017447:Receptors, Dopamine D1; D012640:Seizures / Q000139:chemically induced; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D014407:Tumor Cells, Cultured
D001552:Benzazepines; D002839:Chromans; D015259:Dopamine Agents; D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D016627:Oxidopamine; D003847:Deoxyglucose; C065380:A 68930; D000262:Adenylyl Cyclases; D006220:Haloperidol