(-)-N-(Cyclopropylmethyl)-4,14-dimethoxymorphinan-6-one (2) was synthesized with 4,14-dimethoxy-N-methylmorphinan-6-one (1) as starting material. In vivo and in vitro experiments show 2 (cyprodime) to be a pure opioid receptor antagonist. Some of these tests (opioid receptor binding assays, guinea pig ileal longitudinal muscle preparation, rat and mouse vas deferens preparation, acetic acid writhing antagonism test) indicate that 2 is a selective mu opioid receptor antagonist.

The N-(cyclobutylmethy1)morphinans 12, 19, 20, 21, 27, and 29 and the N-(2-cyanoethyl) analogue 33 were prepared from different precursors. Pharmacological evaluation (e.g. opioid receptor binding assays, acetic-acid writhing test, hot-plate assay) points to a partial opioid agonism of compounds 12, 27, 29, and 33, and to full opioid agonism of compounds 1P-21.

N-Allyl-and N-[(cyclopropyl)methyl]-3,4-dimethoxy-5-methylmorphinan-6-one (9 and 10, resp.) were synthesized from 5-methyldihydrothebainone (1). This essential intermediate was prepared from thebaine via 5-methylthebaine (5) employing a novel route. The pharmacological studies showed 9 and 10 to be potent opioid agonists. Compound 10 was found to have preference for kappa rather than mu opioid receptors.Introduction. -The opioid agonistic properties of N-methylmorphinan-6-ones are very much dependent on the substitution pattern at the aromatic ring [l]. Besides the 'natural' substitution pattern 3-hydroxy-4,5-epoxy, the 4-monomethoxy and the 3,4-dimethoxy substitution was found to be most effective. Among the compounds with high antinociceptive potency was 3,4-dimethoxy-5,17-dimethylrnorphinan-6-one (6) [2], which prompted us to replace its N-CH, group by substituents known to introduce in most cases opioid antagonistic effects in morphinans. We chose the N-ally1 and the N-(cyclopropy1)-methyl group which are present in the opioid antagonists naloxone and naltrexone, respectively.

N-Cyclopropylmethyl- and N-cyclobutylmethylmorphinan-6-one (3 and 4, respectively) were prepared from N-methylmorphinan-6-one. The pharmacological studies showed 3 and 4 to be potent opioid agonists. Compound 3 was found to have preference for kappa rather than mu opioid receptors.

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