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 [(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.
Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709-2194, United States. Electronic address: fic@rti.org.
F Ivy
FI
Carroll
Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709-2194, United States.
Moses G
MG
Gichinga
Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709-2194, United States.
Chad M
CM
Kormos
Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709-2194, United States.
Rangan
R
Maitra
Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709-2194, United States.
Scott P
SP
Runyon
Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709-2194, United States.
James B
JB
Thomas
Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709-2194, United States.
S Wayne
SW
Mascarella
Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709-2194, United States.
Ann M
AM
Decker
Research Triangle Institute, PO Box 12194, Research Triangle Park, NC 27709-2194, United States.
Hernán A
HA
Navarro
D000818:Animals; D002463:Cell Membrane Permeability / Q000187:drug effects; D004285:Dogs; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006207:Half-Life; D061985:Madin Darby Canine Kidney Cells; D009292:Narcotic Antagonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D010880:Piperidines / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D011485:Protein Binding; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D044005:Tetrahydroisoquinolines / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics
C433814:7-hydroxy-N-(1-((4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl)methyl)-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide; D009292:Narcotic Antagonists; D010880:Piperidines; D017473:Receptors, Opioid, kappa; D044005:Tetrahydroisoquinolines; C032727:piperidine
ADME properties; JDTic; Kappa antagonist; Opioids