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

Future Med Chem. 2016 May;8(7):731-49. doi: 10.4155/fmc-2015-0001. Epub 2016 May 10.

Abstract

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 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.

Conclusion: 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.

Keywords: antioxidant; inflammation; pain; positive allosteric modulator; α7 nAChR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Analgesics / chemistry
  • Analgesics / pharmacology*
  • Animals
  • Antioxidants / chemistry
  • Antioxidants / pharmacology*
  • Gene Expression
  • Humans
  • Propane / analogs & derivatives*
  • Propane / chemistry
  • Propane / pharmacology
  • Rats, Wistar
  • Structure-Activity Relationship
  • alpha7 Nicotinic Acetylcholine Receptor / chemistry
  • alpha7 Nicotinic Acetylcholine Receptor / metabolism*

Substances

  • Analgesics
  • Antioxidants
  • alpha7 Nicotinic Acetylcholine Receptor
  • Propane
  • 1,3-diphenylpropane