R(-) and S(+) stereoisomers of 11-hydroxy- and 11-methoxy-N-n-propylnoraporphine: central dopaminergic behavioral activity in the rat.
R(-)11-Hydroxy-N-n-propylnoraporphine (11-OH-NPa) induced stereotyped behavior in the rat as potently (ED50 = 0.80 mg/kg, i.p.) as R(-)apomorphine (APO) and this effect was blocked by haloperidol; the 11-methoxy congener, R(-)11-MeO-NPa, had a weak effect (ED50 greater than 10 mg/kg) and the S(+) isomers had none. The isomer R(-)11-OH-NPa potentiated locomotion stimulated by apomorphine; S(+)11-OH-NPa inhibited it and the isomers of 11-MeO-NPa were inactive. Catecholaporphines usually are inactive orally, but both R(-) and S(+)11-OH-NPa were similarly potent after oral or parenteral administration. The isomer S(+)11-OH-NPa inhibited spontaneous and apomorphine-induced locomotion (ID50 = 1.8-2.7 mg/kg, p.o. and i.p.) and stereotyped behavior (ID50 = 3 mg/kg, p.o. or i.p.), all without inducing catalepsy. While apomorphine was short-acting (1-2 hr), the effects of R(-)11-OH-NPa persisted up to 6-7 hr and those of the S(+) isomer for at least 2.5 hr; moreover, the efficacy of R(-)11-OH-NPa increased markedly up to 3-4 hr, although its ED50 was independent of time (ED50 = 1.7-1.9 mg/kg, i.p. from 1-3 hr). The total effect of R(-)11-OH-NPa (p.o. or i.p.) over time was more than 10-times greater than that of injected apomorphine. These observations accord with the reported high (nM) affinity of 11-OH-NPa at cerebral DA receptor sites (D2 greater than D1) and weak interactions of the 11-methoxy congener. They support the conclusion that the R(-) and S(+) stereoisomers are neuropharmacologically active, respectively, as DA agonist and apparent antagonist, as was found with the enantiomers of N-n-propylnorapomorphine, perhaps due to the low intrinsic postsynaptic agonist activity of the S(+) isomers. Moreover, 11-OH-NPa was highly bioavailable orally and unusually long-acting; it may be absorbed slowly or have active metabolites. Hydroxy-substitution of aporphines at the 11-position, homologous to the 3-OH of DA, evidently is critical for affinity and activity at the DA receptor. These or other monohydroxyaporphines may represent leads to potentially useful DA agonist or antagonist drugs.
Campbell
A
A
Department of Psychiatry, Harvard Medical School, Boston, Massachusetts.
Baldessarini
R J
RJ
Gao
Y
Y
Zong
R
R
Neumeyer
J L
JL
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001060:Aporphines / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D002375:Catalepsy / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects*; D013237:Stereoisomerism; D013239:Stereotyped Behavior / Q000187:drug effects
D014150:Antipsychotic Agents; D001060:Aporphines; D011954:Receptors, Dopamine; C065323:11-methoxy-N-n-propylnoraporphine; C008081:11-hydroxy-N-(n-propyl)noraporphine