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.
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 [(35)S]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 EC(50) (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 [(125)I]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.
Xu
H
H
CPS, NIDA, IRP, NIDA, NIH, Baltimore, Maryland 21224, USA.
Lu
Y F
YF
Thomas
J B
JB
Carroll
F I
FI
Rice
K C
KC
Rothman
R B
RB
D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D016466:CHO Cells / Q000187:drug effects* / Q000378:metabolism; D003001:Cloning, Molecular; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D005260:Female; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D006801:Humans; D009292:Narcotic Antagonists / Q000494:pharmacology; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D011869:Radioligand Assay; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000378:metabolism; D013462:Sulfur Radioisotopes / Q000493:pharmacokinetics
C401942:4-((N-allyl-3-methyl-4-piperidinyl)phenylamino)-N,N-diethylbenzamide; D001549:Benzamides; D009292:Narcotic Antagonists; D010880:Piperidines; D017465:Receptors, Opioid, delta; D013462:Sulfur Radioisotopes; D016244:Guanosine 5'-O-(3-Thiotriphosphate)