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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).
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2018 Sep 13; Vol. 61 (17), pp. 7525-7545. Date of Electronic Publication: 2018 Aug 29. - Publication Year :
- 2018
-
Abstract
- 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 (3 R)-7-hydroxy- N-{(1 S)-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 <subscript>e</subscript> = 0.37 nM in a [ <superscript>35</superscript> 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.
- Subjects :
- Animals
CHO Cells
Cricetulus
Guanosine 5'-O-(3-Thiotriphosphate) metabolism
Humans
Male
Narcotic Antagonists metabolism
Radioligand Assay
Rats, Sprague-Dawley
Receptors, Opioid, delta antagonists & inhibitors
Receptors, Opioid, delta genetics
Receptors, Opioid, delta metabolism
Receptors, Opioid, kappa genetics
Receptors, Opioid, kappa metabolism
Receptors, Opioid, mu antagonists & inhibitors
Receptors, Opioid, mu genetics
Receptors, Opioid, mu metabolism
Structure-Activity Relationship
Brain drug effects
Narcotic Antagonists chemistry
Narcotic Antagonists pharmacology
Receptors, Opioid, kappa antagonists & inhibitors
Tetrahydroisoquinolines chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 61
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 30117738
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.8b00673