2. Academic Validation
  3. Design, synthesis, and pharmacological evaluation of JDTic analogs to examine the significance of the 3- and 4-methyl substituents

Design, synthesis, and pharmacological evaluation of JDTic analogs to examine the significance of the 3- and 4-methyl substituents

  • Bioorg Med Chem. 2015 Oct 1;23(19):6379-88. doi: 10.1016/j.bmc.2015.08.025.
F Ivy Carroll 1,  Moses G Gichinga 2,  Chad M Kormos 2,  Rangan Maitra 2,  Scott P Runyon 2,  James B Thomas 2,  S Wayne Mascarella 2,  Ann M Decker 2,  Hernán A Navarro 2
Affiliations

Affiliations

  • 1 Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709-2194, United States. Electronic address: [email protected].
  • 2 Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709-2194, United States.
PMID: 26342544 DOI: 10.1016/j.bmc.2015.08.025
Abstract

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 [(35)S]GTPγS 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 κ Opioid Receptor antagonists.

Keywords

ADME properties; JDTic; Kappa antagonist; Opioids.

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