Cinnamoyl derivatives of 7a-amino- and 7a-(aminomethyl)- N-(cyclopropylmethyl)-6,14-endo-ethanotetrahydronororipavines are high-potency opioid antagonists

Methods have been developed for the synthesis of 7a-amino- and 7a-(aminomethyl)-N-cyclopropylmethyl-6.14-endo-ethanotetrahydronororipavines and their cinnamoyl derivatives (Schemes 1 and 3). In displacement binding assays, the cinnamoyl derivatives 4c and 5c had high affinity for opioid receptors, but no particular selectivity for any receptor type or differences in affinity between 4c and 5c (Table 1). In tissue assays for opioid receptor function, in which both 4c and 5c were potent antagonists, the aminomethyl derivative 5c was 20- to 70-fold more potent than the amino derivative 4c (Table 2). These data are in keeping with previously reported in vivo data and confirm the major effect of the methylene spacer in 5c.