Aporphines. 14 Dopaminergic and antinociceptive activity of aporphine derivatives. Synthesis of 10-hydroxyaporphines and 10-hydroxy-N-n-propylnoraporphine.

The synthesis of racemic 10-hydroxyaporphine [(+/-)-2a] and 10-hydroxy-N-n-propylnoraporphine [(+/)-2b] is described. The method involved a Reissert alkylation-Pschorr cyclization route. The dopaminergic activity of (+/-)-2b was evaluated in comparison with L-Dopa, (-)-apomorphine (1a), (+/-)-N-n-propylnorapomorphine (NPA) (1b), and (+/-)-11-hydroxy-N-n-propylnoraporphine [(+/-)-11-OH-PNA] by the behavioral model of rotational behavior in animals after unilateral lesion of the ascending DA pathways. The dopaminergic activity of NPA and 11-OH-PNA is essentially equivalent to L-Dopa and (-)-apomorphine, and both are more active than (+/-)-2b. Furthermore, (+/-)-NPA (threshold doses, 5 mug/kg) appears to be even more potent that (-)-apomorphine (threshold doses, 25 mug/kg). The duration of action of NPA and 11-OH-PNA is considerably longer than that obtained with L-Dopa. The antinociceptive activity of (+/-)-2b was evaluated by the tail-flick procedure and compared with 1a, 2b, morphine, and L-Dopa. Weak but significant antinociceptive activity was shown by (+/-)-2b and by (+/-)-1b but not by (-)-apomorphine. This effect was not antagonized by naloxone. The finding that (+/-)-2b and particularly (+/-)-11-OH-PNA are active in doses from 500 to 50 mug/kg, respectively, in causing rotational behavior further supports previous studies indicating that N-n-propyl derivatives of monohydroxylated aporphines were more active than the corresponding parent N-methyl derivatives as DA receptor agonists and that a catechol system is not an absolute requirement for dopaminergic activity in such aporphines.

Physical dependence and tolerance development after chronic exposure to low levels of morphine in the rat.

A sustained-release delivery system containing 14C-morphine was implanted subcutaneously in rats. Measurement of urinary excretion of 14C suggested a steady state release of approximately 640 micrograms 14C morphine/day during a 10-day test period. Tolerance developed rapidly to the analgetic effects produced by an injected ED95 dose of morphine sulfate in implanted rats tested on the hot-plate. Physical dependence, determined by naloxone-precipitated abstinence behavior, was evident in rats at 24 hr. Morphine dosage was estimated to be as low as 2.5 mg/kg/day. Peak abstinence behavior was observed on Day 4. However, naloxone-precipitated withdrawal signs were markedly diminished by Day 6 and essentially absent by Day 8. These results are discussed with reference to the suggestion that metabolic changes, occcurring during chronic exposure to morphine, may explain the lack of abstinence behavior during a time when maximal concentrations of urinary morphine were observed and a high degree of tolerance was manifest.

Antihypertensive effects of delta9-tetrahydrocannabinol.

Repeated oral administration of delta9-tetrahydrocannabinol (delta9-THC, 25 mg/kg) reduced systolic blood pressure in conscious spontaneously hypertensive rats. Tolerance to the antihypertensive actions of delta9-THC failed to develop during the 10-day treatment period. The failure of delta9-THC to alter blood pressure in normotensive rats suggests that the hypotensive action of delta9-THC is dependent, in part, on baseline blood pressure.