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

• Published in: Journal of medicinal chemistry 2014-09, Vol.57 (17), p.7367-7381
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Binding, Competitive; Drug Design; Guanosine 5'-O-(3-Thiotriphosphate) - metabolism; Humans; Hydrogen Bonding; Kinetics; Models, Chemical; Models, Molecular; Molecular Docking Simulation; Molecular Structure; Piperidines - chemical synthesis; Piperidines - metabolism; Piperidines - pharmacology; Radioligand Assay; Receptors, Opioid, kappa - antagonists & inhibitors; Receptors, Opioid, kappa - chemistry; Receptors, Opioid, kappa - metabolism; Tetrahydroisoquinolines - chemical synthesis; Tetrahydroisoquinolines - metabolism; Tetrahydroisoquinolines - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm5008177

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 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.