Design Synthesis and BiologicalEvaluation of (3R)-1234-Tetrahydro-7-hydroxy-N-(1S)-1-(3R4R)-4-(3-hydroxyphenyl)-34-dimethyl-1-piperidinylmethyl-2-methylpropyl-3-isoquinolinecarboxamide(JDTic) Analogues: In Vitro Pharmacology and ADME Profile

摘要

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 [³⁵S]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.