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

• Published in: Future medicinal chemistry Vol. 8; no. 7; pp. 731 - 749
• Main Authors: Criado, Manuel, Balsera, Beatriz, Mulet, José, Sala, Salvador, Sala, Francisco, de la Torre-Martínez, Roberto, Fernández-Carvajal, Asia, Ferrer-Montiel, Antonio, Moreno-Fernández, Silvia, Miguel, Marta, Pérez de Vega, María Jesús, González-Muñiz, Rosario
• Format: Journal Article
• Language: English
• Published: England 01.05.2016
• Subjects: Allosteric Regulation; alpha7 Nicotinic Acetylcholine Receptor - chemistry; alpha7 Nicotinic Acetylcholine Receptor - metabolism; Analgesics - chemistry; Analgesics - pharmacology; Animals; Antioxidants - chemistry; Antioxidants - pharmacology; Gene Expression; Humans; Propane - analogs & derivatives; Propane - chemistry; Propane - pharmacology; Rats, Wistar; Structure-Activity Relationship; antioxidant; pain; inflammation; α7 nAChR; positive allosteric modulator
• ISSN: 1756-8919; 1756-8927
• DOI: 10.4155/fmc-2015-0001

Nicotine acethylcholine receptors (nAChRs) play critical roles in cognitive processes, neuroprotection and inflammation. According to their substituents, 1,3-diphenylpropan-1-one derivatives act as α7 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 μM) 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. Compound 31 is a novel, potent and selective α7 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 nAChR-mediated diseases.