Discovery of a Potent, Peripherally Selective trans-3,4-Dimethyl-4-(3-hydroxyphenyl)piperidine Opioid Antagonist for the Treatment of Gastrointestinal Motility Disorders
| Autor: | Darryle Darwin Schoepp, Buddy E. Cantrell, J. S. Gidda, Dennis M. Zimmerman, J. D. Leander, B G Johnson |
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| Rok vydání: | 1994 |
| Předmět: |
Diarrhea
Male medicine.drug_class Guinea Pigs Receptors Opioid mu In Vitro Techniques Pharmacology δ-opioid receptor Mice Radioligand Assay Structure-Activity Relationship Piperidines Drug Discovery Alvimopan medicine Animals Receptor Chemistry Antagonist Intestinal Diseases Opioid Systemic administration Molecular Medicine μ-opioid receptor Gastrointestinal Motility Opioid antagonist medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 37:2262-2265 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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