CI-1007, a dopamine partial agonist and potential antipsychotic agent. II. Neurophysiological and behavioral effects.
CI-1007 has been described in receptor binding and biochemical tests as a dopamine (DA) partial agonist that exhibits DA autoreceptor agonist effects. The present studies describe the profile of CI-1007 in electrophysiological and behavioral tests. CI-1007 inhibited the firing of substantia nigra DA neurons with intrinsic DA agonist activity that was less than that of the full agonists apomorphine and talipexole but greater than that of the weak partial agonist SDZ 208-912. CI-1007 was more potent after intracerebroventricular versus intraperitoneal injection in inhibiting spontaneous locomotor activity in mice, indicating a central site of action. In rats, CI-1007 inhibited locomotor activity after i.v. and p.o. injection, but did not produce locomotor stimulation or induce stereotypy, indicating a lack of postsynaptic DA agonist activity. The relative potencies of CI-1007 for inhibiting apomorphine-stimulated behaviors versus spontaneous locomotor activity in rodents indicated weak postsynaptic DA antagonist actions, consistent with a partial agonist profile. Similar to known antipsychotics, CI-1007 potently inhibited Sidman avoidance responding in squirrel monkeys, but, in contrast to most available antipsychotics, CI-1007 caused only mild extrapyramidal dysfunction in squirrel and cebus monkeys sensitized to the dystonic effects of haloperidol. These data indicate that CI-1007 is a DA partial agonist of moderate intrinsic activity that activates brain DA autoreceptors, produces behavioral effects predictive of antipsychotic efficacy and has a low liability for induction of extrapyramidal side effects.
Meltzer
L T
LT
Department of Neuroscience Pharmacology, Division of Warner-Lambert Co., Ann Arbor, Michigan, USA.
Christoffersen
C L
CL
Corbin
A E
AE
Ninteman
F W
FW
Serpa
K A
KA
Wiley
J N
JN
Wise
L D
LD
Heffner
T G
TG
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001058:Apomorphine / Q000494:pharmacology; D017660:Autoreceptors / Q000187:drug effects; D001362:Avoidance Learning / Q000187:drug effects; D001480:Basal Ganglia Diseases / Q000139:chemically induced; D018491:Dopamine Agonists / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012453:Saimiri
D014150:Antipsychotic Agents; D017660:Autoreceptors; D018491:Dopamine Agonists; C090025:1,2,3,6-tetrahydro-4-phenyl-1-((3-phenyl-3-cyclohexen-1-yl)methyl)pyridine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D001058:Apomorphine