De novo design, synthesis, and biological activities of high-affinity and selective non-peptide agonists of the delta-opioid receptor.
On the basis of the structure-activity relationships of delta-opioid-selective peptide ligands and on a model of the proposed bioactive conformation for a potent and selective, conformationally constrained delta-opioid peptide ligand [(2S, 3R)-TMT1]DPDPE, a series of small organic peptide mimetic compounds targeted for the delta-opioid receptor have been designed, synthesized, and evaluated in radiolabeled ligand binding assays and in vitro bioassays. The new non-peptide ligands use piperazine as a template to present the most important pharmacophore groups, including phenol and phenyl groups and a hydrophobic moiety. This hydrophobic group was designed to mimic the hydrophobic character of the D-Pen residues in DPDPE, which has been found to be extremely important for increasing the binding affinity and selectivity of these non-peptide ligands for the delta-opioid receptor over the mu-opioid receptor. Compound 6f (SL-3111) showed 8 nM binding affinity and over 2000-fold selectivity for the delta-opioid receptor over the mu-opioid receptor. Both enantiomers of SL-3111 were separated, and the (-)-isomer was shown to be the compound with the highest affinity for the delta-opioid receptor found in our study (IC50 = 4.1 nM), with a selectivity very similar to that observed for the racemic compound. The phenol hydroxyl group of SL-3111 turned out to be essential to maintain high affinity for the delta-opioid receptor, which also was observed in the case of the delta-opioid-selective peptide ligand DPDPE. Binding studies of SL-3111 and [p-ClPhe4]DPDPE on the cloned wild-type and mutated human delta-opioid receptors suggested that the new non-peptide ligand has a binding profile similar to that of DPDPE but different from that of (+)-4-[((alphaR)-alpha(2S,5R)-4-allyl-2, 5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC-80), another delta-opioid-selective non-peptide ligand.
Liao
S
S
Departments of Chemistry and Pharmacology, The University of Arizona, Tucson, Arizona 85721, USA.
Alfaro-Lopez
J
J
Shenderovich
M D
MD
Hosohata
K
K
Lin
J
J
Li
X
X
Stropova
D
D
Davis
P
P
Jernigan
K A
KA
Porreca
F
F
Yamamura
H I
HI
Hruby
V J
VJ
D000818:Animals; D001559:Benzhydryl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D015195:Drug Design; D006168:Guinea Pigs; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018716:Molecular Mimicry; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009154:Mutation; D010455:Peptides / Q000737:chemistry*; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
C115931:1-(4-tert-butyl-3'-hydroxybenzhydryl)-4-benzylpiperazine; D001559:Benzhydryl Compounds; D008024:Ligands; D010455:Peptides; D010879:Piperazines; D017465:Receptors, Opioid, delta