ASYMMETRIC SYNTHESES, OPIOID RECEPTOR AFFINITIES, AND ANTINOCICEPTIVEEFFECTS OF 8-AMINO-5,9-METHANOBENZOCYCLOOCTENES, A NEW CLASS OF STRUCTURAL ANALOGS OF THE MORPHINE ALKALOIDS

Several 8-amino-5,9-methanobenzocyclooctenes have been prepared by asy mmetric 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 ethano-9-(methoxymethyl)-5-methylbenzocyc looctene, (+)-3a vs oxy-5,9-methanoxymethyl)-5-methylbenzocyclooctene, (dl)-22] resulted in a >10-fold increase in kappa-receptor affinity. Antinociceptive studies demonstrated that (dl)-22 was a full kappa-ago nist 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 a t this receptor.