Synthesis and in vitro opioid receptor functional antagonism of methyl-substituted analogues of (3R)-7-hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic).
In previous structure-activity relationship (SAR) studies, (3R)-7-hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic, 3) was identified as the first potent and selective kappa-opioid receptor antagonist from the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of opioid antagonists. In the present study, we report the synthesis of analogues 8a-p of 3 and present their in vitro opioid receptor functional antagonism using a [(35)S]GTPgammaS binding assay. Compounds 8a-p are analogues of 3 containing one, two, or three methyl groups connected to the JDTic structure at five different positions. All the analogues with one and two added methyl groups with the exception of 8k had subnanomolar K(e) values at the kappa receptor. The three most potent analogues were the monomethylated (3R)-7-hydroxy-N-[(1S,2S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidine-1-yl]methyl}-2-methylbutyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (8a) and (3R)-7-hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl}-(2-methylpropyl)]-3-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (8e) with K(e) values of 0.03 nM at the kappa receptor and (3R)-7-hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-methoxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl}-2-methylpropyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (8d) with K(e) = 0.037 nM at the kappa receptor. All three compounds were selective for the kappa receptor relative to the micro and delta receptors. Overall, the results from this study highlight those areas that are tolerant to substitution on 3.
Cueva
Juan Pablo
JP
Center for Organic and Medicinal Chemistry, Research Triangle Institute, Post Office Box 12194, Research Triangle Park, North Carolina 27709-2194, USA.
Cai
Tingwei Bill
TB
Mascarella
S Wayne
SW
Thomas
James B
JB
Navarro
Hernán A
HA
Carroll
F Ivy
FI
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D009292:Narcotic Antagonists; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
C433814:7-hydroxy-N-(1-((4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)methyl)-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide; D009292:Narcotic Antagonists; D010880:Piperidines; D044005:Tetrahydroisoquinolines