Pharmacologic profile of a novel potent direct-acting dopamine agonist, (+)-4-propyl-9-hydroxynaphthoxazine [(+)-PHNO].

Abstract

The (+)-enantiomer of 1,2,3,4a,5,6-hexahydro-9-hydroxy-4-n-propyl-4H-naphth[1,2-b][ 1,4]-oxazine [(+)-PHNO] is demonstrated to be a potent and direct dopamine (DA) agonist in several in vivo and in vitro test procedures. In vitro (+)-PHNO inhibited binding of [3H]apomorphine (IC50 = 23 nM) or [3H]spiperone (IC50 = 55 nM) to rat striatal membranes. Because (+)-PHNO failed to stimulate adenylate cyclase in carp retina, it was classified as a D-2 agonist. ED50 values (shown in parentheses) derived in DA receptor-related in vivo tests were as follows: in mice, (+)-PHNO produced hypothermia (13 micrograms/kg i.p.) and postural asymmetry in the unilaterally caudectomized animal (4 micrograms/kg i.p.). In the rat, (+)-PHNO produced stereotypy (10 micrograms/kg i.p.) and contralateral turning in 6-hydroxydopamine-lesioned animals (5 micrograms/kg i.p.) that lasted 1 to 3 hr. Whereas both of the latter effects were blocked by haloperidol, prior treatment with depletors of endogenous catecholamines, reserpine or alpha-methylparatyrosine failed to reduce (+)-PHNO-induced stereotypy. The naphthoxazine also produced emesis in beagles (0.05 micrograms/kg i.v.) that was blocked by L-646,462, a peripherally selective DA receptor antagonist. (+)-PHNO was well absorbed when given p.o., producing contralateral turning (10 micrograms/kg) with a ratio of p.o. to i.p. ED50 values of 2. This ratio was much lower than those derived for n-propylnorapomorphine (60) and apomorphine (54). At the DA autoreceptor, (+)-PHNO inhibited the accumulation of dOPA in the gamma-butyrolactone-treated rat (11 micrograms/kg i.p.).(ABSTRACT TRUNCATED AT 250 WORDS)

• Authors: G E Martin, M Williams, D J Pettibone, G G Yarbrough, B V Clineschmidt, J H Jones
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 230 Issue 3 Pg. 569-76 (Sep 1984) ISSN: 0022-3565 [Print] United States
• PMID: 6433000 (Publication Type: Journal Article)

Chemical References

• Hydroxydopamines
• Oxazines
• Receptors, Dopamine
• naxagolide
• Spiperone
• Oxidopamine
• Adenylyl Cyclases
• Apomorphine

Topics

• Adenylyl Cyclases (metabolism)
• Animals
• Apomorphine (metabolism)
• Binding, Competitive
• Body Temperature (drug effects)
• Brain Stem (drug effects)
• Female
• Fishes
• Humans
• Hydroxydopamines (pharmacology)
• Mice
• Motor Activity (drug effects)
• Oxazines (pharmacology)
• Oxidopamine
• Posture
• Rats
• Rats, Inbred Strains
• Receptors, Dopamine (metabolism)
• Retina (enzymology)
• Spiperone (metabolism)
• Stereotyped Behavior (drug effects)
• Vomiting (chemically induced)