Pharmacological profile of the dopamine partial agonist, (+/-)-PD 128483 and its enantiomers.
(+/-)-PD 128483, ((+/-)-4,5,5a,6,7,8-hexahydro-6-methylthiazolo[4,5-f]-quinolin+ ++-2-amine, maleate (1:1)), is a racemic compound that is a p.o. active dopamine (DA) partial agonist that has DA autoreceptor agonist effects and displays antipsychoticlike activity in preclinical tests. In in vitro receptor binding assays, (+/-)-PD 128483 and its enantiomers bound selectively to DA D-2 receptors vs. DA D-1 receptors and showed no affinity for adrenergic alpha-1 or serotonin1A receptors, but had affinity for adrenergic alpha-2 receptors. In tests of DA agonist effects, including reversal of the tau-butyrolactone-stimulated increase in brain dopa synthesis in striatum and inhibition of DA neuronal firing, the rank order of efficacy was (+)-PD 128483 > (+/-)-PD 128483 > (-)-PD 128483. (+/-)-PD 128483 and (+)-PD 128483 inhibited, whereas (-)-PD 128483 increased, brain DA synthesis in normal rats. (+/-)-PD 128483 and (-)-PD 128483 inhibited spontaneous locomotion in rats and did not produce locomotor stimulation or stereotypies. In contrast, (+)-PD 128483 inhibited locomotor activity at low doses, but at relatively high doses increased locomotion and induced stereotypy in rats. (-)-PD 128483 consistently inhibited Sidman avoidance responding in squirrel monkeys. (+/-)-PD 128483 inhibited Sidman avoidance responding in one group of monkeys, but had minimal effects in another group. (+)-PD 128483 did not inhibit avoidance responding. In squirrel or cebus monkeys sensitized to the acute dystonic effects of haloperidol, only (-)-PD 128483 induced extrapyramidal dysfunction. These results indicate that (+/-)-PD 128483 is a DA partial agonist which produces DA autoreceptor agonist effects and has a preclinical behavioral profile suggestive of antipsychotic activity.
Meltzer
L T
LT
Department of Pharmacology, Parke-Davis Pharmaceutical Research, Warner-Lambert Company, Ann Arbor, Michigan.
Caprathe
B W
BW
Christoffersen
C L
CL
Corbin
A E
AE
Jaen
J C
JC
Ninteman
F W
FW
Pugsley
T A
TA
Serpa
K A
KA
Shih
Y H
YH
Whetzel
S Z
SZ
D015107:4-Butyrolactone / Q000494:pharmacology; D000634:Aminoquinolines / Q000378:metabolism / Q000494:pharmacology*; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D002428:Cebus; D004298:Dopamine / Q000096:biosynthesis / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005116:Extrapyramidal Tracts / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000378:metabolism; D012453:Saimiri; D012701:Serotonin / Q000096:biosynthesis / Q000378:metabolism; D013237:Stereoisomerism; D013239:Stereotyped Behavior / Q000187:drug effects; D013268:Stimulation, Chemical; D013844:Thiazoles / Q000378:metabolism / Q000494:pharmacology*
D000634:Aminoquinolines; D015259:Dopamine Agents; D011954:Receptors, Dopamine; D013844:Thiazoles; C073971:PD 128483; D012701:Serotonin; D000661:Amphetamine; D001058:Apomorphine; D015107:4-Butyrolactone; D004298:Dopamine; D009638:Norepinephrine