Nicotinic acetylcholine receptor ligands, a patent review (2006-2011)

Abstract

Introduction: Nicotinic acetylcholine receptors (nAChRs), pentameric ligand-gated cation channels, are potential targets for the development of therapeutics for a variety of disease states.

Areas covered: This article is reviewing recent advances in the development of small-molecule ligands for diverse nAChR subtypes and is a continuation of an earlier review in this journal.

Expert opinion: The development of nAChR ligands with preference for α4β2 or α7 subtypes for the treatment of central nervous system disorders are in the most advanced developmental stage. In addition, there is a fast growing interest to generate so-called PAMs, positive allosteric modulators, to influence the channels' functionalities.

Figure 1

The endogenous ligands choline (Ch) and acetylcholine (ACh), natural lead compounds nicotine, epibatidine, ferruginine, anatoxin-a, and cytisine, and the approved drug varenicline.

Figure 2

Compounds with an acyclic cationic center.

Figure 3

Azetidine based ligands.

Figure 4

Pyrrolidine based compounds.

Figure 5

Compounds bearing diverse N-containing six- or seven-cyclic systems as cationic centers.

Figure 6

Bicyclo-heptanes.

Figure 7

Azabicyclo-octanes.

Figure 8

Diazabicyclo-octanes.

Figure 9

Quinuclidines.

Figure 10

Bicyclo[3.3.0]octanes.

Figure 11

Bicyclononanes I.

Figure 12

Bicyclononanes II.

Figure 13

Azadecanes and adamantanes.

Figure 14

α4β2 PAMs

Figure 15

α7 PAMs I

Figure 16

α7 PAMs II

Figure 17

α7 PAMs III