Investigation of the N-substituent conformation governing potency and mu receptor subtype-selectivity in (+)-(3R, 4R)-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonists
| Autor: | S. W. Mascarella, Heng Xu, Frank I. Carroll, James B. Thomas, John S. Partilla, Richard B. Rothman, K. B. Mccullough, D. M. Zimmerman, B. E. Cantrell, Christina M. Dersch |
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| Rok vydání: | 1998 |
| Předmět: |
Stereochemistry
medicine.drug_class Narcotic Antagonists Guinea Pigs Substituent Molecular Conformation Receptors Opioid mu In Vitro Techniques Crystallography X-Ray Chemical synthesis chemistry.chemical_compound Piperidines Opioid receptor Receptors Opioid delta Drug Discovery medicine Potency Animals Binding site Receptors Opioid kappa Brain Rats chemistry Guanosine 5'-O-(3-Thiotriphosphate) Molecular Medicine Stereoselectivity Piperidine Selectivity |
| Zdroj: | Journal of medicinal chemistry. 41(11) |
| ISSN: | 0022-2623 |
| Popis: | A study of the binding site requirements associated with the N-substituent of (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (4) derivatives was undertaken using a set of rigid vs flexible N-substituents. The study showed that compounds 7-9 bearing the trans-cinnamyl N-substituent most closely reproduced the potency at the opioid receptor of the flexible N-propylphenyl or N-propylcyclohexyl analogues previously reported. Neither the N-substituted cis-cinnamyl nor the cis-phenylcyclopropylmethyl compounds 10 and 11, respectively, showed high affinity for the opioid receptor. However, the N-trans-phenylcyclopropylmethyl compound 12 closely approximated the affinity of compounds 7-9. Additionally, we found that free rotation of the phenyl ring is necessary for high affinity binding and mu receptor subtype selectivity as the planar N-substituted thianaphthylmethyl and benzofuranylmethyl compounds 13 and 14 had significantly lower binding affinities. Altogether, these findings suggest that the high binding affinity, selectivity, and antagonist potency of N-propylphenyl or N-propylcyclohexyl analogues of (+)-(3R, 4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (4) are achieved via a conformation wherein the connecting chain of the N-substituents is extended away from piperidine nitrogen with the appended ring system rotated out-of-plane relative to the connecting chain atoms. This conformation is quite similar to that observed in the solid state for 5, as determined by single crystal X-ray analysis. Additionally, it was found that, unlike naltrexone, N-substituents bearing secondary carbons attached directly to the piperidine nitrogen of 4 suffer dramatic losses of potency vs analogues not substituted in this manner. Using a functional assay which measured stimulation or inhibition of [35S]GTP-gamma-S binding, we show that the trans-cinnamyl analogues of (+)-(3R, 4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (4) retain opioid pure antagonist activity and possess picomolar antagonist potency at the mu receptor. |
| Databáze: | OpenAIRE |
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