1,3-diphenylpropan-1-ones as allosteric modulators of α7 nACh receptors with analgesic and antioxidant properties

被引：14

作者：

Criado, Manuel ^{[1
]}

Balsera, Beatriz ^{[2
]}

Mulet, Jose ^{[1
]}

Sala, Salvador ^{[1
]}

Sala, Francisco ^{[1
]}

de la Torre-Martinez, Roberto ^{[3
]}

Fernandez-Carvajal, Asia ^{[3
]}

Ferrer-Montiel, Antonio ^{[3
]}

Moreno-Fernandez, Silvia ^{[4
]}

Miguel, Marta ^{[4
]}

Perez de Vega, Maria Jesus ^{[2
]}

Gonzalez-Muniz, Rosario ^{[2
]}

机构：

[1] Univ Miguel Hernandez CSIC, Inst Neurociencias, Sant Joan dAlacant 03050, Spain

[2] IQM CSIC, Inst Quim Med, Juan Cierva 3, Madrid 28006, Spain

[3] Univ Miguel Hernandez, Inst Biol Mol & Celular, Ave Univ S-N, Elche 03202, Alicante, Spain

[4] CEI UAM, CSIC UAM, Inst Invest Ciencias Alimentac, C Nicolas Cabrera 9, Madrid 28049, Spain

来源：

FUTURE MEDICINAL CHEMISTRY | 2016年 / 8卷 / 07期

关键词：

alpha; 7; nAChR; antioxidant; inflammation; pain; positive allosteric modulator; NICOTINIC ACETYLCHOLINE-RECEPTOR; VITRO PHARMACOLOGICAL CHARACTERIZATION; IN-VIVO; NEUROPATHIC PAIN; VAGUS NERVE; 4-(5-(4-CHLOROPHENYL)-2-METHYL-3-PROPIONYL-1H-PYRROL-1-YL)BENZENESULFONAMIDE A-867744; ANTIINFLAMMATORY PATHWAY; COGNITIVE DEFICITS; FLAVONOIDS; DISCOVERY;

D O I：

10.4155/fmc-2015-0001

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Nicotine acethylcholine receptors (nAChRs) play critical roles in cognitive processes, neuroprotection and inflammation. Results: According to their substituents, 1,3-diphenylpropan-1-one derivatives act as alpha 7 nAChRs negative allosteric modulators (NAM, OMe) or Type I positive allosteric modulators (PAMs, OH). Compounds 7 and 31 were the most effective (989 and 666% enhancement of ACh-induced currents) and potent (EC50 : 12.9 and 6.85 mu M) PAMs. They exhibited strong radical scavenging values. Compound 31, selective over other neuronal nAChR subtypes and with acceptable pharmacokinetic profile, showed antinociceptive effects in a model of inflammatory pain. Conclusion: Compound 31 is a novel, potent and selective alpha 7 nAChR PAM, displaying antioxidant and analgesic activities. The 1,3-diphenylpropan-1-one scaffold could be the base toward more advanced type I PAMs for the treatment of n-AChR-mediated diseases.

引用

页码：731 / 749

页数：19

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