Synthesis and muscarinic activity of a series of quinolines and naphthalenes with a 1-azabicyclo[3.3.0]octane moiety

Chem Pharm Bull (Tokyo). 1998 Aug;46(8):1265-73. doi: 10.1248/cpb.46.1265.

Abstract

In order to discover a medicine effective against Alzheimer's disease, we synthesized a series of quinoline derivatives having a characteristic 1-azabicyclo[3.3.0]octane amine ring, and performed pharmacological evaluation of them. Acetylcholine esterase inhibitory activities of these derivatives were unexpectedly weak. Tests for central nervous muscarinic cholinergic receptor binding affinity indicated that these compounds had higher affinities to muscarinic M1 receptors than to M2 receptors. A series of naphthalene derivatives substituted with the 1-azabicyclo[3.3.0]octane ring were also synthesized and muscarinic M1 and M2 receptor binding affinity determined. These compounds had much higher affinity for M1 receptors than the quinoline derivatives, and 1-[N-(1-azabicyclo[3.3.0]octan-5-yl)methyl-N-methylamino]-4-nitronaph tha lene showed the highest affinity and selectivity. The ability of this compound to improve cognitive function was assessed using the passive avoidance test in scopolamine-induced mice.

MeSH terms

  • Animals
  • Avoidance Learning / drug effects
  • Aza Compounds / chemical synthesis
  • Aza Compounds / metabolism
  • Aza Compounds / pharmacology
  • Cholinergic Agents / chemical synthesis*
  • Cholinergic Agents / metabolism
  • Cholinergic Agents / pharmacology*
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / metabolism
  • Cholinesterase Inhibitors / pharmacology
  • Cognition / drug effects
  • Dementia / chemically induced
  • Dementia / drug therapy
  • Disease Models, Animal
  • Kinetics
  • Male
  • Mice
  • Mice, Inbred Strains
  • Naphthalenes / chemical synthesis*
  • Naphthalenes / pharmacology*
  • Quinolines / chemical synthesis*
  • Quinolines / metabolism
  • Quinolines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Muscarinic M1
  • Receptor, Muscarinic M2
  • Receptors, Muscarinic / drug effects
  • Receptors, Muscarinic / metabolism
  • Structure-Activity Relationship

Substances

  • Aza Compounds
  • Cholinergic Agents
  • Cholinesterase Inhibitors
  • Naphthalenes
  • Quinolines
  • Receptor, Muscarinic M1
  • Receptor, Muscarinic M2
  • Receptors, Muscarinic