N-substituted 4beta-methyl-5-(3-hydroxyphenyl)-7alpha-amidomorphans are potent, selective kappa opioid receptor antagonists |
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Authors: | Carroll F Ivy Melvin Matt S Nuckols Michel C Mascarella S Wayne Navarro Hernán A Thomas James B |
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Institution: | Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, North Carolina 27709, USA. fic@rti.org |
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Abstract: | In a previous study, we identified (-)-N-(1R,4S,5S,7R)-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenylpropyl)-2-azabicyclo3.3.1]non-7-yl]-3-(1-piperidinyl)propanamide (5a, KAA-1) as the first potent and selective kappa opioid receptor antagonist from the 5-(3-hydroxyphenyl)morphan class of opioids. In this study we report an improved synthesis of this class of compounds. The new synthetic method was used to prepare analogues 5b-r where the morphan N-substituent and 7alpha-amido group were varied. Most of the analogues showed sub-nanomolar potency for the kappa opioid receptor and were highly selective relative to the mu and delta opioid receptors. (-)-3-(3,4-Dihydroisoquinolin-2(1H)-yl)-N-{(1R,4S,5S,7R)-5-(3-hydroxyphenyl)-4-methyl-2-2-(2-methylphenyl)ethyl]-2-azabicyclo3.3.1]non-7-yl}propanamide (5n, MTHQ) is at least as potent and selective as nor-BNI as a kappa opioid receptor antagonist in the 35S]GTP-gamma-S in vitro functional test. |
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