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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). Synthesis and in vitro and in vivo opioid receptor antagonist activity.
J Med Chem. 2010 Jul 22; 53(14):5290-301.JM

Abstract

The synthesis of compounds 6, 7a,b, 8a,b, 9a,b, and 10a,b where the amino -NH- group of JDTic (3) was replaced with an aromatic horizontal lineCH-, CH(2), O, S, or SO group was accomplished and used to further characterize the SAR of the compound 3 class of kappa opioid receptor antagonists. All of the compounds showed subnanomolar to low nanomolar K(e) values at the kappa opioid receptor. The most potent compound was 7a, where the amino -NH- group of 3 was replaced by a methylene (-CH(2)-) group. This compound had a K(e) = 0.18 nM and was 37- and 248-fold selective for the kappa relative to the mu and delta opioid receptors, respectively. Similar to compound 3, compound 7a antagonized selective kappa agonist U50,488-induced diuresis after sc administration in rats. In contrast to 3, where kappa antagonist activity lasted for three weeks, compound 7a did not show any kappa antagonist activity after one week.

Authors+Show Affiliations

Organic and Medicinal Chemistry, Research Triangle Institute, 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 available

Pub Type(s)

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

Language

eng

PubMed ID

20568781

Citation

Runyon, Scott P., et al. "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). Synthesis and in Vitro and in Vivo Opioid Receptor Antagonist Activity." Journal of Medicinal Chemistry, vol. 53, no. 14, 2010, pp. 5290-301.
Runyon SP, Brieaddy LE, Mascarella SW, et al. 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). Synthesis and in vitro and in vivo opioid receptor antagonist activity. J Med Chem. 2010;53(14):5290-301.
Runyon, S. P., Brieaddy, L. E., Mascarella, S. W., Thomas, J. B., Navarro, H. A., Howard, J. L., Pollard, G. T., & Carroll, F. I. (2010). 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). Synthesis and in vitro and in vivo opioid receptor antagonist activity. Journal of Medicinal Chemistry, 53(14), 5290-301. https://doi.org/10.1021/jm1004978
Runyon SP, et al. 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). Synthesis and in Vitro and in Vivo Opioid Receptor Antagonist Activity. J Med Chem. 2010 Jul 22;53(14):5290-301. PubMed PMID: 20568781.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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). Synthesis and in vitro and in vivo opioid receptor antagonist activity. AU - Runyon,Scott P, AU - Brieaddy,Lawrence E, AU - Mascarella,S Wayne, AU - Thomas,James B, AU - Navarro,Hernán A, AU - Howard,James L, AU - Pollard,Gerald T, AU - Carroll,F Ivy, PY - 2010/6/24/entrez PY - 2010/6/24/pubmed PY - 2010/8/26/medline SP - 5290 EP - 301 JF - Journal of medicinal chemistry JO - J Med Chem VL - 53 IS - 14 N2 - The synthesis of compounds 6, 7a,b, 8a,b, 9a,b, and 10a,b where the amino -NH- group of JDTic (3) was replaced with an aromatic horizontal lineCH-, CH(2), O, S, or SO group was accomplished and used to further characterize the SAR of the compound 3 class of kappa opioid receptor antagonists. All of the compounds showed subnanomolar to low nanomolar K(e) values at the kappa opioid receptor. The most potent compound was 7a, where the amino -NH- group of 3 was replaced by a methylene (-CH(2)-) group. This compound had a K(e) = 0.18 nM and was 37- and 248-fold selective for the kappa relative to the mu and delta opioid receptors, respectively. Similar to compound 3, compound 7a antagonized selective kappa agonist U50,488-induced diuresis after sc administration in rats. In contrast to 3, where kappa antagonist activity lasted for three weeks, compound 7a did not show any kappa antagonist activity after one week. SN - 1520-4804 UR - https://www.unboundmedicine.com/medline/citation/20568781/Analogues_of__3R__7_hydroxy_N_[_1S__1_{[_3R4R__4__3_hydroxyphenyl__34_dimethyl_1_piperidinyl]methyl}_2_methylpropyl__1234_tetrahydro_3_isoquinolinecarboxamide__JDTic___Synthesis_and_in_vitro_and_in_vivo_opioid_receptor_antagonist_activity_ L2 - https://doi.org/10.1021/jm1004978 DB - PRIME DP - Unbound Medicine ER -