Probes for narcotic receptor mediated phenomena. 23. Synthesis, opioid receptor binding, and bioassay of the highly selective delta agonist (+)-4-[(alpha R)-alpha-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]- N,N-diethylbenzamide (SNC 80) and related novel nonpeptide delta opioid receptor ligands.
The highly selective delta (delta) opioid receptor agonist SNC 80 [(+)-4- [(alpha R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N ,N- diethylbenzamide, (+)-21] and novel optically pure derivatives were synthesized from the enantiomers of 1-allyl-trans-2,5-dimethylpiperazine (2). The piperazine (+/-)-2 was synthesized, and its enantiomers were obtained on a multigram scale in > 99% optical purity by optical resolution of the racemate with the camphoric acids. The absolute configuration of (+)-2 was determined to be 2S,5R by X-ray analysis of the salt with (+)-camphoric acid. Since the chirality of the starting material was known, and the relative configuration of compounds (-)-21, (-)-22, and (+)-23 were obtained by single-crystal X-ray analysis, the assignment of the absolute stereochemistry of the entire series could be made. Radioreceptor binding studies in rat brain preparations showed that methyl ethers (+)-21 (SNC 80) and (-)-25 exhibited strong selectivity for rat delta receptors with low nanomolar affinity to delta receptors and only micromolar affinity for rat mu (mu) opioid receptors. Compounds (-)-21, (-)-22, and (-)-23 showed micromolar affinities for delta opioid receptors. The unsubstituted derivative (+)-22 and the fluorinated derivative (-)-27 showed > 2659- and > 2105-fold delta/mu binding selectivity, respectively. The latter derivatives are the most selective ligands described in the new series. Studies with some of the compounds described in the isolated mouse vas deferens and guinea pig ileum bioassays revealed that all were agonists with different degrees of selectivity for the delta opioid receptor. These data show that (+)-21 and (+)-22 are potent delta receptor agonists and suggest that these compounds will be valuable tools for further study of the delta opioid receptor at the molecular level, including its function and role in analgesia and drug abuse.
Calderon
S N
SN
Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Rice
K C
KC
Rothman
R B
RB
Porreca
F
F
Flippen-Anderson
J L
JL
Kayakiri
H
H
Xu
H
H
Becketts
K
K
Smith
L E
LE
Bilsky
E J
EJ
Davis
P
P
Horvath
R
R
D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D018360:Crystallography, X-Ray; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D016308:Enkephalin, Leucine-2-Alanine / Q000378:metabolism; D004745:Enkephalins / Q000378:metabolism; D006168:Guinea Pigs; D007082:Ileum / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008968:Molecular Conformation; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism; D013237:Stereoisomerism; D014649:Vas Deferens / Q000378:metabolism
D001549:Benzamides; D004745:Enkephalins; D010879:Piperazines; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C083877:BW 373U86; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide; D016308:Enkephalin, Leucine-2-Alanine