Pharmacological profile of SCH39166: a dopamine D1 selective benzonaphthazepine with potential antipsychotic activity.
SCH39166 [(-)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl- 5H-benzo[d]naptho-(2,1-b)azepine] is a benzonaphthazepine that has been evaluated as a selective D1 dopamine receptor antagonist. In vitro, SCH39166 (Ki = 3.6 nM) inhibited the binding of [3H]SCH23390 (a D1 specific compound) and blocked dopamine-stimulated adenylate cyclase (Ki = 9.1 nM); in contrast the Ki for SCH39166 to displace [3H]spiperone (D2) was greater than 1 microM and its Ki vs. [3H]-ketanserin (5-hydroxytryptamine2) binding was greater than 300 nM. In vivo, SCH39166 inhibited both rat and squirrel monkey conditioned avoidance responding (minimal effective dose = 10 and 1.78 mg/kg p.o., respectively) and had a duration of at least 6 hr in both species. In addition, SCH39166 antagonized apomorphine-induced stereotypy in rats (minimal effective dose = 10 mg/kg p.o.). These in vivo actions of SCH39166 are similar to the activity of typical dopamine antagonists. However, in contrast to D2-selective antagonists, SCH39166 failed to increase plasma prolactin levels, did not block apomorphine-induced emesis in the dog and had minimal effects on the striatal levels of homovanillic acid or dihydroxyphenylacetic acid. Furthermore, although immobility was seen after p.o. administration of SCH39166 using the inclined screen test, the drug did not cause catalepsy at doses up to 10 times its minimal effective dose in the rat conditioned avoidance response test. Additionally, SCH39166 inhibited apomorphine-induced climbing at lower doses than it inhibited apomorphine-induced sniffing in mice. The results from these latter two tests suggest that SCH39166 may have a reduced liability to produce extrapyramidal side effects. Therefore, based on this profile of activity, SCH39166 is a selective D1 dopamine receptor antagonist both in vitro and in vivo. Additionally, because this compound is longer acting in the primate than previously available D1 antagonists, it has potential utility as a clinically useful drug.
Chipkin
R E
RE
Research Division, Schering-Plough Corporation, Bloomfield, New Jersey.
Iorio
L C
LC
Coffin
V L
VL
McQuade
R D
RD
Berger
J G
JG
Barnett
A
A
D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis; D000262:Adenylyl Cyclases / Q000032:analysis; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001058:Apomorphine / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects; D001552:Benzazepines / Q000494:pharmacology*; D002375:Catalepsy / Q000139:chemically induced; D004285:Dogs; D004298:Dopamine / Q000032:analysis; D018492:Dopamine Antagonists; D006719:Homovanillic Acid / Q000032:analysis; D008297:Male; D051379:Mice; D011388:Prolactin / Q000097:blood; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects*; D017447:Receptors, Dopamine D1; D013239:Stereotyped Behavior / Q000187:drug effects; D014839:Vomiting / Q000517:prevention & control
D014150:Antipsychotic Agents; D001552:Benzazepines; D018492:Dopamine Antagonists; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; C058081:ecopipam; D015102:3,4-Dihydroxyphenylacetic Acid; D011388:Prolactin; D000262:Adenylyl Cyclases; D001058:Apomorphine; D004298:Dopamine; D006719:Homovanillic Acid