Design, synthesis, and pharmacological evaluation of JDTic analogs to examine the significance of the 3-and 4-methyl substituents
The design and discovery of JDTic as a potent and selective kappa opioid receptor antagonist used the N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl) piperidine pharmacophore as the lead structure. In order to determine if the 3-methyl or 4-methyl groups were necessary in JDTic and JDTic analogs for antagonistic activity, compounds 4a-c, and 4d-f which have either the 3-methyl or both the 3- and 4-methyl groups removed, respectively, from JDTic and analogs were synthesized and evaluated for their in vitro opioid receptor antagonist activities using a [S-35] GTP gamma S binding assay. Other ADME properties were also assessed for selected compounds. These studies demonstrated that neither the 3-methyl or 3,4-dimethyl groups present in JDTic and analogs are required to produce potent and selective kappa opioid receptor antagonists. (C) 2015 Elsevier Ltd. All rights reserved.
Carroll, F. I., Gichinga, M. G., Kormos, C. M., Maitra, R., Runyon, S. P., Thomas, J. B., ... Navarro, H. A. (2015). Design, synthesis, and pharmacological evaluation of JDTic analogs to examine the significance of the 3-and 4-methyl substituents. Bioorganic and Medicinal Chemistry, 23(19), 6379-6388. https://doi.org/10.1016/j.bmc.2015.08.025