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 [concentration producing 50% inhibition] = 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 [median effective dose] values (shown in parentheses) derived in DA receptor-related in vivo tests were as follows: in mice, (+)-PHNO produced hypothermia (13 .mu.g/kg i.p.) and postural asymmetry in the unilaterally caudectomized animal (4 .mu.g/kg i.p.). In the rat, (+)-PHNO produced stereotypy (10 .mu.g/kg i.p.) and contralateral turning in 6-hydroxydopamine-lesioned animals (5 .mu.g/kg i.p.) that lasted 1 to 3 h. 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 .mu.g/kg i.v.) that was blocked by L-646,462, a peripherally selective DA receptor antagonist. (+)-PHNO was well absorbed when given p.o. [orally], producing contralateral turning (10 .mu.g/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 the autoreceptor, (+)-PHNO inhibited the accumulation of dOPA in the .gamma.-butyrolactone-treated rat (11 .mu.g/kg i.p.). It also reduced the locomotor activity of the mouse (ID30% = 25 .mu.g/kg i.p.) in a sulpiride (10 mg/kg i.p.) but not yohimbine (0.67 mg/kg i.p.) reversible fashion. The DA autoreceptor selectivity index (ED50 stereotype/ED50 .gamma.-butyrolactone) was 1.1 for (+)-PHNO, suggesting no selectivity for the DA autoreceptor. The i.v. administration of (+)-PHNO inhibited the firing of brain stem DA neurons in a haloperidol-reversible fashion. (+)-PHNO was more potent than standard DA agonists in the aforementioned in vivo tests, except n-propylnorapomorphine that was equipotent in producing turning or stereotype in rats. (+)-PHNO is one of the most potent DA agonists yet discovered.