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Opioid peptide receptor studies. 15. Relative efficacy of 4‐[(N‐allyl‐3‐methyl‐4‐piperidinyl)phenylamino]‐ N,N ‐diethylbenzamide and related compounds at the cloned human δ‐opioid receptor
Author(s) -
Xu Heng,
Lu YiFeng,
Thomas James B.,
Carroll F. Ivy,
Rice Kenner C.,
Rothman Richard B.
Publication year - 2001
Publication title -
synapse
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.809
H-Index - 106
eISSN - 1098-2396
pISSN - 0887-4476
DOI - 10.1002/syn.1049
Subject(s) - agonist , chemistry , δ opioid receptor , piperidine , stereochemistry , receptor , partial agonist , opioid receptor , opioid , intrinsic activity , pharmacology , biochemistry , biology
Previous data obtained from both binding and functional assays demonstrated that (−)‐4‐[(N‐allyl‐3‐methyl‐4‐piperidinyl)phenylamino]‐ N,N ‐diethylbenzamide [(−)‐RTI5989‐54] displays selective binding and full agonist activity relative to (±)‐RTI5989‐54 for the δ opioid receptor. The present study was conducted to evaluate the activities of structurally diverse opioid receptor δ ligands in the [ 35 S]GTP‐γ‐S binding assay, comparing the relationship between receptor binding, activation, efficacy, and intrinsic efficacy. The data, obtained with cloned human δ receptors, demonstrated that (−)‐RTI5989‐54 behaves like the highly selective δ agonist SNC80. Addition of the hydroxyl group to RTI5989‐54 (RTI5989‐61) or replacement of the allyl group with the trans‐crotyl group on the piperidine nitrogen of RTI‐5989‐61 (RTI5989‐62) increased binding affinity, produced full agonist activity, and decreased intrinsic efficacy at the δ opioid receptor. The order of potency for the EC 50 (GTP‐γ‐S) was RTI5989‐62 (0.20 nM) > RTI5989‐61 (0.43 nM) > SNC80 (1.92 nM) > DPDPE (3.50 nM) > (−)‐RTI5989‐54 (17.6 nM) > (±)‐RTI5989‐54 (65.6 nM) > (+)‐RTI5989‐54 (483 nM). RTI5989‐61 and RTI5989‐62 were fully efficacious, but had intrinsic efficacy values that were 2.2–3.1 times lower than that of DPDPE and SNC80. Comparison of the binding K i in competitively inhibiting [ 125 I]IOXY binding to the functional K i for δ antagonists [Ki (IOXY)/Ki (GTP‐γ‐S)] shows that antagonists might antagonize agonist‐evoked neurochemical effects with equal magnitude while occupying different proportions of target receptors. Synapse 40:269–274, 2001. © 2001 Wiley‐Liss, Inc.