Highly potent and selective phenylmorphan-based inverse agonists of the opioid delta receptor.
We recently reported the discovery of (+)-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenylpropyl)-2-azabicyclo[3.3.1]non-7-yl-(1-phenyl-1-cyclopentane)carboxamide [(+)-KF4, (+)-5] as a novel chemotype possessing potent antagonist activity at the delta opioid receptor. Additional SAR studies involving changes to both the 2-amino and 7-amido N-substituents using this same (+)-morphan scaffold have revealed compounds with improved potency and selectivity for the delta opioid receptor. The highly potent and selective 2,2-dimethylphenylacetamide analogue (+)-N-[(1S,4R,5R,7S)-5-(3-hydroxyphenyl)-4-methyl-2-(3-phenylpropyl)-2-azabicyclo[3.3.1]non-7-yl]-2-methyl-2-phenylpropanamide (13d, delmorphan-A) showed picomolar inhibitory potency (Ke = 0.1 nM) in the [35S]GTPgammaS functional assay with delta opioid receptor selectivity ratios of 103- and 132-fold versus the mu and kappa opioid receptors, respectively. The compounds showed no agonist activity at any of the three opioid receptors; however, measurements of delta inverse agonist activity within this series illustrated a broad range of negative efficacy and IC50 values 650-fold more potent than the prototypical delta opioid receptor inverse agonist ICI 174,864 (22).
Thomas
James B
JB
Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, North Carolina 27709, USA.
Zhang
Li
L
Navarro
Hernan A
HA
Carroll
F Ivy
FI
D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D011869:Radioligand Assay; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D019086:Bridged Bicyclo Compounds, Heterocyclic; C514069:N-(5-(3-hydroxyphenyl)-4-methyl-2-(3-phenylpropyl)-2-azabicyclo(3.3.1)non-7-yl)-2-methyl-2-phenylpropanamide; D017465:Receptors, Opioid, delta