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

Abstract

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.