A general synthetic approach to a novel series of cis-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ols is described together with their receptor-binding profile on opioid-receptor subtypes (mu, kappa, delta). In addition, their in vivo antinociceptive activity was assessed. A number of the analogues synthesized showed potent affinity for opioid receptors and have potent antinociceptive activity in a mouse phenylquinone abdominal stretching model. In addition, the SAR for nitrogen substitution in the above series is explored with respect to the overall opioid receptor subtype binding profile. In general it was found that substituents which enhanced mu and kappa binding affinity in the benzomorphan series had a similar effect in the benzofuropyridine series described in this manuscript. An overlap hypothesis topologically connecting the benzomorphan nucleus to the cis-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridine nucleus is also presented.
A series of azaspiro[4.5]decanyl amides were prepared by a novel cyclization route and examined for opiate receptor binding and antinociceptive activity. Selected tertiary amides in this series showed potent selective mu-receptor binding and antinociceptive activity, in contrast to the less conformationally restricted secondary amides, which showed relatively weak activity. Although structurally similar to the kappa-agonist U-50488H (1), these compounds showed virtually no tendency to bind to the kappa-receptor. An X-ray crystal structure of compound (21) confirms that the spirocyclic amine does not cause distortion away from the chair conformation of the cyclohexane ring. Either this receptor has very specific requirements for the orientation of the two nitrogens of these compounds or this ring system fills a portion of space more readily tolerated by the mu- and delta-receptors.
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