Probes for narcotic receptor mediated phenomena. 23. Synthesis, opioid receptor binding, and bioassay of the highly selective δ agonist (+)-4- [(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]N,N- diethylbenzamide (SNC 80) and related novel nonpeptide δ opioid receptor ligands

Silvia N. Calderon, Kenner C. Rice, Richard B. Rothman, Frank Porreca, Judith L. Flippen-Anderson, Hiroshi Kayakiri, Heng Xu, Karen Becketts, Larren E. Smith, Edward J. Bilsky, Peg Davis, Robert Horvath

Research output: Contribution to journalArticle

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Abstract

The highly selective delta (δ) opioid receptor agonist SNC 80 [(+)-4- [(αR)-α-((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 δ receptors with low nanomolar affinity to 6 receptors and only micromolar affinity for rat mu (μ) opioid receptors. Compounds (- )-21, (-)-22, and (-)-23 showed micromolar affinities for δ opioid receptors. The unsubstituted derivative (+)-22 and the fluorinated derivative (-)-27 showed >2659- and >2105-fold δ/μ 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 δ opioid receptor. These data show that (+)-21 and (+)-22 are potent δ receptor agonists and suggest that these compounds will be valuable tools for further study of the δ opioid receptor at the molecular level, including its function and role in analgesia and drug abuse.

Original languageEnglish (US)
Pages (from-to)695-704
Number of pages10
JournalJournal of Medicinal Chemistry
Volume40
Issue number5
DOIs
StatePublished - Feb 28 1997

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Bioassay
Opioid Receptors
Biological Assay
Ligands
Derivatives
Rats
Enantiomers
X ray analysis
X-Rays
Methyl Ethers
delta Opioid Receptor
Acids
Vas Deferens
mu Opioid Receptor
Ileum
Analgesia
Stereochemistry
Substance-Related Disorders
Chirality
Guinea Pigs

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Probes for narcotic receptor mediated phenomena. 23. Synthesis, opioid receptor binding, and bioassay of the highly selective δ agonist (+)-4- [(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]N,N- diethylbenzamide (SNC 80) and related novel nonpeptide δ opioid receptor ligands. / Calderon, Silvia N.; Rice, Kenner C.; Rothman, Richard B.; Porreca, Frank; Flippen-Anderson, Judith L.; Kayakiri, Hiroshi; Xu, Heng; Becketts, Karen; Smith, Larren E.; Bilsky, Edward J.; Davis, Peg; Horvath, Robert.

In: Journal of Medicinal Chemistry, Vol. 40, No. 5, 28.02.1997, p. 695-704.

Research output: Contribution to journalArticle

Calderon, Silvia N. ; Rice, Kenner C. ; Rothman, Richard B. ; Porreca, Frank ; Flippen-Anderson, Judith L. ; Kayakiri, Hiroshi ; Xu, Heng ; Becketts, Karen ; Smith, Larren E. ; Bilsky, Edward J. ; Davis, Peg ; Horvath, Robert. / Probes for narcotic receptor mediated phenomena. 23. Synthesis, opioid receptor binding, and bioassay of the highly selective δ agonist (+)-4- [(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]N,N- diethylbenzamide (SNC 80) and related novel nonpeptide δ opioid receptor ligands. In: Journal of Medicinal Chemistry. 1997 ; Vol. 40, No. 5. pp. 695-704.
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AU - Calderon, Silvia N.

AU - Rice, Kenner C.

AU - Rothman, Richard B.

AU - Porreca, Frank

AU - Flippen-Anderson, Judith L.

AU - Kayakiri, Hiroshi

AU - Xu, Heng

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