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.

ABSTRACT: JDTic analogues 4-15 which have the hydroxyl groups replaced with other groups were synthesized and their in vitro efficacy at the ?, ?, and ? opioid receptors determined and compared to JDTic using [(35)S]GTP?S 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 ? receptor and were highly selective for the ? receptor relative to the ? and ? 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 ? opioid receptors 4, 5, 13, and 14 deserve consideration for further development toward potential drugs for CNS disorders.

SUBMITTER: Kormos CM 

PROVIDER: S-EPMC4161151 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature