Novel delta opioid receptor agonists exhibit differential stimulation of signaling pathways.
A novel family of 1,3,5-trisubstituted 1,2,4-triazoles was discovered as potent and selective ligands for the delta opioid receptor by rational design. Compound 5b exhibited low-nanomolar in vitro binding affinity (IC(50)=5.8 nM), excellent selectivity for the delta opioid receptor over the alternative mu and kappa opioid receptors, full agonist efficacy in receptor down-regulation and MAP kinase activation assays, and low-efficacy partial agonist activity in stimulation of GTPgammaS binding. The apparent discrepancy observed in these functional assays may stem from different signaling pathways involved in each case, as found previously for other G-protein coupled receptors. More biological studies are underway to better understand the differential stimulation of signaling pathways by these novel compounds.
Peng
Youyi
Y
Department of Pharmacology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School and the Informatics Institute of UMDNJ, Piscataway, NJ 08854, United States.
Zhang
Qiang
Q
Arora
Sonia
S
Keenan
Susan M
SM
Kortagere
Sandhya
S
Wannemacher
Kenneth M
KM
Howells
Richard D
RD
Welsh
William J
WJ
D020134:Catalytic Domain; D002454:Cell Differentiation; D002460:Cell Line; D003198:Computer Simulation; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008968:Molecular Conformation; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D017465:Receptors, Opioid, delta; D014230:Triazoles; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D020928:Mitogen-Activated Protein Kinases