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 delta-opioid receptor
Xu, H., Lu, Y. F., Thomas, J., Carroll, F., Rice, K. C., & Rothman, R. B. (2001). 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 delta-opioid receptor. Synapse, 40(4), 269-274.
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 delta opioid receptor. The present study was conducted to evaluate the activities of structurally diverse opioid receptor delta ligands in the [S-35]GTP-gamma -S binding assay, comparing the relationship between receptor binding, activation, efficacy, and intrinsic efficacy. The data, obtained with cloned human delta receptors, demonstrated that (-)-RTI5989-54 behaves like the highly selective delta 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 delta opioid receptor. The order of potency for the EC50 (GTP-gamma -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 [I-125]IOXY binding to the functional K-i for delta antagonists [Ki (IOXY)/Ki (GTP-gamma -S)] shows that antagonists might antagonize agonist-evoked neurochemical effects with equal magnitude while occupying different proportions of target receptors. Synapse 40:289-274, 2001, (C) 2001 Wiley-Liss, Inc.dagger