Design, synthesis, and biological evaluation of (3 R)-1,2,3,4-tetrahydro-7-hydroxy- N -[(1 S)-1-[[(3 R,4 R)-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 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 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 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.