Agonist and antagonist properties of benzazepine and thienopyridine derivatives at the D1 dopamine receptor.
Nine structurally related 1-phenyl-1H-3-benzazepine derivatives and two thienopyridines were tested for agonist and antagonist properties at the adenylate cyclase-coupled D1 dopamine receptor in homogenates of the striatum of the rat. The benzazepines SK&F 77434 and SK&F 82958, both of which contain a catechol ring, were agonists; the intrinsic activity of SK&F 77434 was similar to that of SK&F 38393, whereas SK&F 82958 was a full agonist. The remaining benzazepines inhibited the stimulation of adenylate cyclase by dopamine. Antagonist potency depended on the nature of the substituent at position 7 of the benzazepine molecule, 7-halogen compounds being the most potent. The Ki values, obtained from analysis of the antagonism of dopamine-stimulated adenylate cyclase, were significantly correlated with the Ki values for displacement of D1 ligands in binding experiments. Furthermore, antagonist activity of the resolved racemic benzazepine SK&F 83566 resided almost exclusively in the R-enantiomer. The thienopyridine derivatives SK&F 89641 and SK&F 89145 were partial agonists with greater efficacies than SK&F 38393.
O'Boyle
K M
KM
Department of Clinical Pharmacology, Royal College of Surgeons, Dublin, Ireland.
Gaitanopoulos
D E
DE
Brenner
M
M
Waddington
J L
JL
D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology; D015259:Dopamine Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects*; D013329:Structure-Activity Relationship
D000067956:Adenylyl Cyclase Inhibitors; D001552:Benzazepines; D015259:Dopamine Agents; D011725:Pyridines; D011954:Receptors, Dopamine