May 24, 2014

Discovery of N-sulfonyl-7-azaindoline derivatives as potent, orally available and selective M(4) muscarinic acetylcholine receptor agonists

Bioorganic & Medicinal Chemistry Letters
Atsushi SuwaTakaaki Sumiyoshi

Abstract

We designed and synthesized novel N-sulfonyl-7-azaindoline derivatives as selective M4 muscarinic acetylcholine receptor agonists. Modification of the N-carbethoxy piperidine moiety of compound 2, an M4 muscarinic acetylcholine receptor (mAChR)-preferring agonist, led to compound 1, a selective M4 mAChR agonist. Compound 1 showed a highly selective M4 mAChR agonistic activity with weak hERG inhibition in vitro. A pharmacokinetic study of compound 1 in vivo revealed good bioavailability and brain penetration in rats. Compound 1 reversed methamphetamine-induced locomotor hyperactivity in rats (1-10 mg/kg, po).

  • References14
  • Citations2

Mentioned in this Paper

Behavior, Animal
Piperidine
Derivatives
Structure-Activity Relationship
Methamphetamine Measurement
Piperidines
Sulfonamides
Metabolic Inhibition
Receptor, Muscarinic M4
Madrine

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