1027905-05-0Relevant articles and documents
Synthesis and biological evaluation of novel delta (δ) opioid receptor ligands with diazatricyclodecane skeletons
Loriga, Giovanni,Lazzari, Paolo,Ruiu, Stefania,Marchese, Giorgio,Manca, Ilaria,Casu, Gian Luca,Dessì, Christian,Pinna, Gérard Aimè,Asproni, Battistina,Murineddu, Gabriele
, p. 413 - 426 (2013/10/22)
Considering the interesting pharmacological profile of the delta (δ) selective opioid agonist compound SNC-80, conformationally constrained analogs containing two diazatricyclodecane ring systems in place of dimethylpiperazine core motif were synthesized.
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
, p. 695 - 704 (2007/10/03)
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.
Probes for narcotic receptor-mediated phenomena. 25.1 Synthesis and evaluation of N-alkyl-substituted (α-piperazinylbenzyl)benzamides as novel, highly selective δ opioid receptor agonists
Katsura, Yousuke,Zhang, Xiaoyan,Homma, Koichi,Rice, Kenner C.,Calderon, Silvia N.,Rothman, Richard B.,Yamamura, Henry I.,Davis, Peg,Flippen-Anderson, Judith L.,Xu, Heng,Becketts, Karen,Foltz, Eric J.,Porreca, Frank
, p. 2936 - 2947 (2007/10/03)
A series of N-alkyl- and N,N-dialkyl-4-[α-{(2S,5R)-4-allyl-2,5- dimethyl-1-piperazinyl}benzyl]-benzamides were synthesized and evaluated for binding affinities at μ, δ, and κ opioid receptor subtypes. Several compounds (2e,f,h,i,m) strongly bound to the δ receptor with IC50 values in the nanomolar range. On the other hand, the binding affinities of these compounds for the μ and κ receptors were in the micromolar or greater range indicating excellent δ opioid receptor subtype selectivities. In this series, two important structure-activity relationships were found for the δ receptor binding affinity. First, the spatial orientation of the α-benzylic position influenced the affinities with the αR derivatives 2a-n generally showing more than 10-fold greater affinity than the αS derivatives 3a-n. Second, the binding affinities were strongly influenced by the number of alkyl substituents on the amide nitrogen. N-Monoalkylbenzamide derivatives 2b-d showed lower affinity than N,N-dialkylbenzamide derivatives 2e-n, and the N-unsubstituted benzamide derivative 2a had the lowest affinity for the δ receptor in the series. The dramatic effect of the amide group substitution pattern on the binding affinity for the δ receptor strongly suggests that the amide function is an important structural element in the interaction of this series of compounds at the δ receptor. Selective compounds in this series were examined for binding affinity in cloned human μ and δ receptors. The results obtained generally paralleled those from the rat brain binding assay. Compounds 2e,f with potent δ binding affinities and high δ selectivities were shown to be δ agonists with high selectivity by studies in the guinea pig ileum (GPI) and mouse vas deferens (MVD) preparations. Compound 2f was the most selective compound in the rat brain and GPI/MVD assays with 1755- and 958-fold δ vs μ selectivity, respectively.
