Design, Synthesis, and Biological Evaluation of (3R)-1,2,3,4-Tetrahydro-7-hydroxy-N-[(1S)-1-[[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl]-3-isoquinolinecarboxamide (JDTic) Analogues: In Vitro Pharmacology and ADME Profile
| Autor: | Kormos, Chad M., Gichinga, Moses G., Maitra, Rangan, Runyon, Scott P., Thomas, James B., Brieaddy, Lawrence E., Mascarella, S. Wayne, Navarro, Hernán A., Carroll, F. Ivy |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: | |
| Zdroj: | Journal of Medicinal Chemistry |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | JDTic analogues 4-15 which have the hydroxyl groups replaced with other groups were synthesized and their in vitro efficacy at the μ, δ, and κ opioid receptors determined and compared to JDTic using [(35)S]GTPγS assays. Compounds 4, 5, 6, 13, 14, and 15 had Ke = 0.024, 0.01, 0.039, 0.02, 0.11, and 0.041 nM compared to the Ke = 0.02 nM for JDTic at the κ receptor and were highly selective for the κ receptor relative to the μ and δ opioid receptors. Unexpectedly, replacement of the 3-hydroxyl substituent of the 4-(3-hydroxyphenyl) group of JDTic with a H, F, or Cl substituent leads to potent and selective KOR antagonists. In vitro studies to determine various ADME properties combined with calculated TPSA, clogP, and logBB values suggests that the potent and selective κ opioid receptors 4, 5, 13, and 14 deserve consideration for further development toward potential drugs for CNS disorders. |
| Databáze: | OpenAIRE |
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