Positive and negative modulation of nicotinic receptors.

摘要: Nicotinic acetylcholine receptors (AChRs) are one of the best characterized ion channels from Cys-loop receptor superfamily. The study binding proteins and prokaryotic different species has been paramount for understanding structure–function relationship AChR function can be modulated by ligand types. neurotransmitter ACh other agonists trigger conformational changes in receptor, finally opening intrinsic cation channel. so-called gating process couples binding, located at extracellular portion, to channel, transmembrane region. After agonist activation, prolonged presence agonists, becomes desensitized. Competitive antagonists overlap agonist-binding sites inhibiting pharmacological action agonists. Positive allosteric modulators (PAMs) do not bind orthostetic but allosterically enhance activity elicited increasing (type I) and/or decreasing desensitization II). Instead, negative (NAMs) produce opposite effects. Interestingly, this effect is similar that found another class drugs, is, noncompetitive (NCAs). However, main difference between both categories drugs based on their distinct site locations. Although NAMs NCAs sites, NACs whereas nonluminal sites. classification less clear interacting extracellular–transmembrane interface where channel mouth might involved. PAMs developed as potential medications treatment several diseases involving AChRs, including dementia-, skin-, immunological-related diseases, drug addiction, cancer. More exciting combination specific with PAMs. we still beginning how these compounds act used therapeutically.