193217-31-1Relevant academic research and scientific papers
New diarylmethylpiperazines as potent and selective nonpeptidic δ opioid receptor agonists with increased in vitro metabolic stability
Plobeck,Delorme,Wei,Yang,Zhou,Schwarz,Gawell,Gagnon,Pelcman,Schmidt,Yue,Walpole,Brown,Zhou,Labare,Payza,St-Ogne,Kamassah,Morin,Projean,Ducharme,Roberts
, p. 3878 - 3894 (2007/10/03)
Nonpeptide δ opioid agonists are analgesics with a potentially improved side-effect and abuse liability profile, compared to classical opioids. Andrews analysis of the NIH nonpeptide lead SNC-80 suggested the removal of substituents not predicted to contribute to binding. This approach led to a simplified lead, N,N-diethyl-4-[phenyl(1-piperazinyl)methyl]benzamide (1), which retained potent binding affinity and selectivity to the human δ receptor (IC50 = 11 nM, μ/δ = 740, κ/δ > 900) and potency as a full agonist (EC50 = 36 nM) but had a markedly reduced molecular weight, only one chiral center, and increased in vitro metabolic stability. From this lead, the key pharmacophore groups for δ receptor affinity and activation were more clearly defined by SAR and mutagenesis studies. Further structural modifications on the basis of 1 confirmed the importance of the N,N-diethylbenzamide group and the piperazine lower basic nitrogen for δ binding, in agreement with mutagenesis data. A number of piperazine N-alkyl substituents were tolerated. In contrast, modifications of the phenyl group led to the discovery of a series of diarylmethylpiperazines exemplified by N,N-diethyl-4-[1-piperazinyl(8-quinolinyl)-methyl]benzamide (56) which had an improved in vitro binding profile (IC50 = 0.5 nM, μ/δ = 1239, EC50 = 3.6 nM) and increased in vitro metabolic stability compared to SNC-80.
Compounds with analgesic effect
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, (2008/06/13)
PCT No. PCT/SE96/01635 Sec. 371 Date Apr. 24, 1997 Sec. 102(e) Date Apr. 24, 1997 PCT Filed Dec. 11, 1996 PCT Pub. No. WO97/23466 PCT Pub. Date Jul. 3, 1997Compounds of the formula (I) as well as their pharmaceutically acceptable salts, and pharmaceutical compositions comprising the novel compounds. The novel compounds of the formula (I) are useful in the management of pain.
