Tags

Type your tag names separated by a space and hit enter

Identification 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 as a novel potent and selective opioid kappa receptor antagonist.
J Med Chem. 2003 Jul 03; 46(14):3127-37.JM

Abstract

(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) was identified as a potent and selective kappa opioid receptor antagonist. Structure-activity relationship (SAR) studies on JDTic analogues revealed that the 3R,4R stereochemistry of the 3,4-dimethyl-4-(3-hydroxyphenyl)piperidine core structure, the 3R attachment of the 7-hydroxy-1,2,3,4-tetrahydroisoquinoline group, and the 1S configuration of the 2-methylpropyl (isopropyl) group were all important to its kappa potency and selectivity. The results suggest that, like other kappa opioid antagonists such as nor-BNI and GNTI, JDTic requires a second basic amino group to express potent and selective kappa antagonist activity in the [(35)S]GTPgammaS functional assay. However, unlike previously reported kappa antagonists, JDTic also requires a second phenol group in rigid proximity to this second basic amino group. The potent and selective kappa antagonist properties of JDTic can be rationalized using the "message-address" concept wherein the (3R,4R)-3,4-dimethyl-4-(hydroxyphenyl)piperidinyl group represents the message, and the basic amino and phenol group in the N substituent constitutes the address. It is interesting to note the structural commonality (an amino and phenol groups) in both the message and address components of JDTic. The unique structural features of JDTic will make this compound highly useful in further characterization of the kappa receptor.

Authors+Show Affiliations

Chemistry and Life Sciences, Research Triangle Institute, 3040 Cornwallis Road, Research Triangle Park, North Carolina 27709, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12825951

Citation

Thomas, James B., et al. "Identification 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 as a Novel Potent and Selective Opioid Kappa Receptor Antagonist." Journal of Medicinal Chemistry, vol. 46, no. 14, 2003, pp. 3127-37.
Thomas JB, Atkinson RN, Vinson NA, et al. Identification 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 as a novel potent and selective opioid kappa receptor antagonist. J Med Chem. 2003;46(14):3127-37.
Thomas, J. B., Atkinson, R. N., Vinson, N. A., Catanzaro, J. L., Perretta, C. L., Fix, S. E., Mascarella, S. W., Rothman, R. B., Xu, H., Dersch, C. M., Cantrell, B. E., Zimmerman, D. M., & Carroll, F. I. (2003). Identification 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 as a novel potent and selective opioid kappa receptor antagonist. Journal of Medicinal Chemistry, 46(14), 3127-37.
Thomas JB, et al. Identification 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 as a Novel Potent and Selective Opioid Kappa Receptor Antagonist. J Med Chem. 2003 Jul 3;46(14):3127-37. PubMed PMID: 12825951.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Identification 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 as a novel potent and selective opioid kappa receptor antagonist. AU - Thomas,James B, AU - Atkinson,Robert N, AU - Vinson,N Ariane, AU - Catanzaro,Jennifer L, AU - Perretta,Carin L, AU - Fix,Scott E, AU - Mascarella,S Wayne, AU - Rothman,Richard B, AU - Xu,Heng, AU - Dersch,Christina M, AU - Cantrell,Buddy E, AU - Zimmerman,Dennis M, AU - Carroll,F Ivy, PY - 2003/6/27/pubmed PY - 2003/8/9/medline PY - 2003/6/27/entrez SP - 3127 EP - 37 JF - Journal of medicinal chemistry JO - J Med Chem VL - 46 IS - 14 N2 - (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) was identified as a potent and selective kappa opioid receptor antagonist. Structure-activity relationship (SAR) studies on JDTic analogues revealed that the 3R,4R stereochemistry of the 3,4-dimethyl-4-(3-hydroxyphenyl)piperidine core structure, the 3R attachment of the 7-hydroxy-1,2,3,4-tetrahydroisoquinoline group, and the 1S configuration of the 2-methylpropyl (isopropyl) group were all important to its kappa potency and selectivity. The results suggest that, like other kappa opioid antagonists such as nor-BNI and GNTI, JDTic requires a second basic amino group to express potent and selective kappa antagonist activity in the [(35)S]GTPgammaS functional assay. However, unlike previously reported kappa antagonists, JDTic also requires a second phenol group in rigid proximity to this second basic amino group. The potent and selective kappa antagonist properties of JDTic can be rationalized using the "message-address" concept wherein the (3R,4R)-3,4-dimethyl-4-(hydroxyphenyl)piperidinyl group represents the message, and the basic amino and phenol group in the N substituent constitutes the address. It is interesting to note the structural commonality (an amino and phenol groups) in both the message and address components of JDTic. The unique structural features of JDTic will make this compound highly useful in further characterization of the kappa receptor. SN - 0022-2623 UR - https://www.unboundmedicine.com/medline/citation/12825951/Identification_of__3R__7_hydroxy_N___1S__1_[[_3R4R__4__3_hydroxyphenyl___34_dimethyl_1_piperidinyl]methyl]_2_methylpropyl__1234_tetrahydro__3_isoquinolinecarboxamide_as_a_novel_potent_and_selective_opioid_kappa_receptor_antagonist_ L2 - https://doi.org/10.1021/jm030094y DB - PRIME DP - Unbound Medicine ER -