Asymmetric syntheses, opioid receptor affinities, and antinociceptive effects of 8-amino-5,9-methanobenzocyclooctenes, a new class of structural analogues of the morphine alkaloids.

Abstract

Several 8-amino-5,9-methanobenzocyclooctenes have been prepared by asymmetric organic synthesis techniques. Opioid receptor affinity studies have revealed the virtual absence of enantioselectivity for receptor binding, particularly at the mu-receptor, for the (+)-3a-f and the (-)-3a-f series. It is noteworthy that inversion of configuration at the nitrogen-bearing carbon atom [5S,8S,9S)-8-amino-3-hydroxy-5, 9-methano-9-(methoxymethyl)-5-methylbenzocyclooctene, (+)-3a vs (5S,8S,9R)-8-amino-3-hydroxy-5, 9-methano-9-(methoxymethyl)-5-methylbenzocyclooctene, (dl)-22] resulted in a > 10-fold increase in kappa-receptor affinity. Antinociceptive studies demonstrated that (dl)-22 was a full kappa-agonist while (+)-3a and (-)-3a did not possess kappa-activity. Although both (dl)-22 and (+)-3a/(-)-3a had high affinity for the mu-receptor, these compounds did not act as high-affinity agonists or antagonists at this receptor.