Discovery of a potent, peripherally selective trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonist for the treatment of gastrointestinal motility disorders.

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Zimmerman DM, Gidda JS, Cantrell BE, Schoepp DD, Johnson BG, Leander JD

Discovery of a potent, peripherally selective trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonist for the treatment of gastrointestinal motility disorders.

J Med Chem. 1994 Jul 22;37(15):2262-5.

PubMed ID

8057274 [ View in PubMed

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Abstract

Structure-activity relationship studies were pursued within N-substituted-trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines in an effort to discover a peripherally selective opioid antagonist with high activity following systemic administration. Altering the size and the polarity of the N-substituent led to the discovery of 3 (LY246736). Compound 3 has high affinity for opioid receptors (Ki = 0.77, 40, and 4.4 nM for mu, kappa, and delta receptors, respectively). It is a potent mu receptor antagonist following parenteral and oral administration and distributes selectively (> 200-fold selectivity) to peripheral receptors. Thus, 3 has properties suitable for the clinical investigation of mu opioid receptor involvement in GI motility disorders.

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