Probes for narcotic receptor mediated phenomena 49. N-substituted rac-cis-4a-arylalkyl-1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ols

• Synthesis of cis-4a-arylalkyl 1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ols.
• Binding studies determined opioid receptor affinity; [35S]GTP-γ-S assays evaluated efficacy.
• Compounds were synthesized with μ- and δ-antagonist activity, and κ-agonist activity.
• An N-allyl substituent in the C4a (CH2)3Ph series gave a μ/δ ratio of 6.
• An N-CPM, C4a (CH2)3Ph substituted compound showed potent δ-antagonist activity.

Racemic N-substituted -1,2,3,4,4a,9a-hexahydrobenzofuro[2,3-c]pyridin-6-ols containing cis-4a-aralkyl groups were explored as probes for opioid receptors. Specifically cis-4a-phenylpropyl, -phenylbutyl, and-phenylpentyl groups coupled with widely varied substituents on the nitrogen atom were synthesized and their pharmacological profiles at opioid receptors examined. The study yielded compounds with good affinity and moderate to potent antagonist activity at the μ- and δ-opioid receptors, and agonist activity at the κ-opioid receptor. An N-allyl substituent in the C4a phenylpropyl series induced 6-fold higher affinity at δ-than μ-receptors, while an N-CPM substituent in the C4a (CH2)3Ph series led to a compound with high δ-affinity and potent δ-antagonist activity.

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