Design, Synthesis, and Biological Evaluation of (3R)-1,2,3,4-Tetrahydro-7-hydroxy-N-[(1S)-1-[[(3R,4R)-4-(3-hydroniphenyl)-3,4-dimethyl-1-piperidinyl]methyl]-2-methylpropyl]-3-isoquinolinecarboxamide (JDTic) Analogues: In Vitro Pharmacology and ADME Profile

JDTic analogues 4-15 which have the hydroxyl groups replaced with other groups were synthesized and their in vitro efficacy at the mu, delta, and kappa opioid receptors determined and compared to JDTic using [S-35]GTP gamma S assays. Compounds 4, 5, 6, 13, 14, and 15 had K-e = 0.024, 0.01, 0.039, 0.02, 0.11, and 0.041 nM compared to the K-e = 0.02 nM for JDTic at the kappa receptor and were highly selective for the kappa receptor relative to the mu and delta 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 kappa opioid receptors 4, 5, 13, and 14 deserve consideration for further development toward potential drugs for CNS disorders.