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Synthesis and in vitro opioid receptor functional antagonism of analogues of the selective kappa opioid receptor antagonist (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).
J Med Chem. 2008 Mar 27; 51(6):1849-60.JM

Abstract

In previous structure-activity relationship (SAR) studies, we identified (3 R)-7-hydroxy- N-((1 S)-1-{[(3 R,4 R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic, 1) as the first potent and selective kappa opioid receptor antagonist from the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of opioid antagonist. In the present study, we report the synthesis and in vitro opioid receptor functional antagonism of a number of analogues of 1 using a [ (35) S]GTPgammaS binding assay. The results from the studies better define the pharmacophore for this class of kappa opioid receptor antagonist and has identified new potent and selective kappa antagonist. (3 R)-7-Hydroxy- N-[(1 S,2 S)-1-{[(3 R,4 R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl}-2-methylbutyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (3) with a K e value of 0.03 nM at the kappa receptor and 100- and 793-fold selectivity relative to the mu and delta receptors was the most potent and selective kappa opioid receptor antagonist identified.

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Authors+Show Affiliations

Cai TB
Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, NC 27709, USA.
Zou Z
No affiliation info available
Thomas JB
No affiliation info available
Brieaddy L
No affiliation info available
Navarro HA
No affiliation info available
Carroll FI
No affiliation info available

MeSH

HumansMolecular StructurePiperidinesReceptors, Opioid, deltaReceptors, Opioid, kappaReceptors, Opioid, muStereoisomerismStructure-Activity RelationshipTetrahydroisoquinolines

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

18307295

Citation

Cai, Tingwei Bill, et al. "Synthesis and in Vitro Opioid Receptor Functional Antagonism of Analogues of the Selective Kappa Opioid Receptor Antagonist (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)." Journal of Medicinal Chemistry, vol. 51, no. 6, 2008, pp. 1849-60.
Cai TB, Zou Z, Thomas JB, et al. Synthesis and in vitro opioid receptor functional antagonism of analogues of the selective kappa opioid receptor antagonist (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). J Med Chem. 2008;51(6):1849-60.
Cai, T. B., Zou, Z., Thomas, J. B., Brieaddy, L., Navarro, H. A., & Carroll, F. I. (2008). Synthesis and in vitro opioid receptor functional antagonism of analogues of the selective kappa opioid receptor antagonist (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). Journal of Medicinal Chemistry, 51(6), 1849-60. https://doi.org/10.1021/jm701344b
Cai TB, et al. Synthesis and in Vitro Opioid Receptor Functional Antagonism of Analogues of the Selective Kappa Opioid Receptor Antagonist (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). J Med Chem. 2008 Mar 27;51(6):1849-60. PubMed PMID: 18307295.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Synthesis and in vitro opioid receptor functional antagonism of analogues of the selective kappa opioid receptor antagonist (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). AU - Cai,Tingwei Bill, AU - Zou,Zhou, AU - Thomas,James B, AU - Brieaddy,Larry, AU - Navarro,Hernán A, AU - Carroll,F Ivy, Y1 - 2008/02/29/ PY - 2008/3/1/pubmed PY - 2008/6/12/medline PY - 2008/3/1/entrez SP - 1849 EP - 60 JF - Journal of medicinal chemistry JO - J Med Chem VL - 51 IS - 6 N2 - In previous structure-activity relationship (SAR) studies, we identified (3 R)-7-hydroxy- N-((1 S)-1-{[(3 R,4 R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic, 1) as the first potent and selective kappa opioid receptor antagonist from the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of opioid antagonist. In the present study, we report the synthesis and in vitro opioid receptor functional antagonism of a number of analogues of 1 using a [ (35) S]GTPgammaS binding assay. The results from the studies better define the pharmacophore for this class of kappa opioid receptor antagonist and has identified new potent and selective kappa antagonist. (3 R)-7-Hydroxy- N-[(1 S,2 S)-1-{[(3 R,4 R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]methyl}-2-methylbutyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (3) with a K e value of 0.03 nM at the kappa receptor and 100- and 793-fold selectivity relative to the mu and delta receptors was the most potent and selective kappa opioid receptor antagonist identified. SN - 0022-2623 UR - https://www.unboundmedicine.com/medline/citation/18307295/Synthesis_and_in_vitro_opioid_receptor_functional_antagonism_of_analogues_of_the_selective_kappa_opioid_receptor_antagonist__3R__7_hydroxy_N___1S__1_{[_3R4R__4__3_hydroxyphenyl__34_dimethyl_1_piperidinyl]methyl}_2_methylpropyl__1234_tetrahydro_3_isoquinolinecarboxamide__JDTic__ L2 - https://doi.org/10.1021/jm701344b DB - PRIME DP - Unbound Medicine ER -
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