Structure-activity relationships of trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine antagonists for mu- and kappa-opioid receptors.

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Zimmerman DM, Leander JD, Cantrell BE, Reel JK, Snoddy J, Mendelsohn LG, Johnson BG, Mitch CH

Structure-activity relationships of trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine antagonists for mu- and kappa-opioid receptors.

J Med Chem. 1993 Oct 1;36(20):2833-41.

PubMed ID

8410998 [ View in PubMed

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Abstract

A series of racemic N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines were evaluated for opioid agonist and antagonist activity at mu and kappa receptors. Several highly potent mu and kappa antagonists were discovered; however, no compounds with high selectivity for either the mu or kappa receptor were identified. Importantly, no derivative was found to have significant opioid agonist activity. Two derivatives were resolved, and the activities of the enantiomers were investigated. Only a limited stereochemical effect on opioid receptor selectivities was observed. The structure-activity relationships described establish the existence of an important lipophilic binding site distal to the nitrogen for both mu and kappa receptors and confirm the pure opioid antagonist pharmacophore nature of the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine structure.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Naloxone	Kappa-type opioid receptor	Ki (nM)	66	N/A	N/A	Details