Potent and Selective Tetrahydroisoquinoline Kappa Opioid Receptor Antagonists of Lead Compound (3 R)-7-Hydroxy- N-[(1 S)-2-methyl-1-(piperidin-1-ylmethyl)propyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (PDTic)
| Autor: | Timothy R. Fennell, F. Ivy Carroll, Pauline W. Ondachi, James B. Thomas, Ann M. Decker, S. Wayne Mascarella, Hernán A. Navarro, Rodney W. Snyder, Scott P. Runyon, Chad M. Kormos |
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| Rok vydání: | 2018 |
| Předmět: |
Male
medicine.drug_class Stereochemistry Narcotic Antagonists Receptors Opioid mu Carboxamide CHO Cells 01 natural sciences κ-opioid receptor Article Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound Radioligand Assay Structure-Activity Relationship 0302 clinical medicine Cricetulus Opioid receptor Receptors Opioid delta Tetrahydroisoquinolines Drug Discovery medicine Structure–activity relationship Animals Humans Receptor 010405 organic chemistry Tetrahydroisoquinoline Receptors Opioid kappa Brain 0104 chemical sciences chemistry Opioid Guanosine 5'-O-(3-Thiotriphosphate) Molecular Medicine Lead compound 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 61(17) |
| ISSN: | 1520-4804 |
| Popis: | Past studies have shown that it has been difficult to discover and develop potent and selective κ opioid receptor antagonists, particularly compounds having potential for clinical development. In this study, we present a structure—activity relationship (SAR) study of a recently discovered new class of tetrahydroisoquinoline κ opioid receptor antagonists which led to (3R)-7-hydroxy-N-{(1S)-2-methyl-1-[(−4-methylpiperidine-1-yl)methyl]propyl}−1,2,3,4-tetrahydroisoquinoline-3-carboxamide (12) (4-Me-PDTic). Compound 12 had a K(e) = 0.37 nM in a [(35)S]GTPγS binding assay and was 645- and >8100-fold selective for the κ relative to the μ and δ opioid receptors, respectively. Calculated log BB and CNS (central nervous system) multiparameter optimization (MPO) and low molecular weight values all predict that 12 will penetrate the brain, and pharmacokinetic studies in rats show that 12 does indeed penetrate the brain. |
| Databáze: | OpenAIRE |
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