Nicotinic agonist

A nicotinic agonist is a drug that mimics the action of acetylcholine (ACh) at nicotinic acetylcholine receptors (nAChRs). The nAChR is named for its affinity for nicotine. A nicotinic agonist is a drug that mimics the action of acetylcholine (ACh) at nicotinic acetylcholine receptors (nAChRs). The nAChR is named for its affinity for nicotine. Examples include nicotine (by definition), acetylcholine (the endogenous agonist of nAChRs), choline, epibatidine, lobeline, varenicline and cytisine. Nicotine has been known for centuries for its intoxicating effect. It was first isolated in 1828 from the tobacco plant by German chemists Posselt and Reimann. The discovery of positive effects from nicotine on animal memory was discovered by in vivo researches in the mid 1980s. Those researches led to a new era in studies of nicotinic acetylcholine receptor (nAChR) and their stimulation but until then the focus had mainly been on nicotine addiction. The development of nAChR agonists began in the early 1990s after the discovery of nicotine's positive effects. Some research showed a possible therapy option in preclinical researches. ABT-418 was one of the first in a series of nAChR agonists and it was designed by Abbott Labs. ABT-418 showed significant increase of delayed matching-to-sample (DMTS) performance in matured macaque apes of different species and sex. ABT-418 has also been examined as a possible treatment to Alzheimer's disease, Parkinson's disease and attention-deficit hyperactivity disorder: those experiments showed positive outcomes. One of the first nAChR active compounds, besides nicotine, that was marketed as a drug was galantamine, a plant alkaloid that works as a weak cholinesterase inhibitor (IC50=5µM) as well as an allosteric sensitizer for nAChRs (EC50=50 nM). In the human nervous system nicotinic cholinergic signals are extended throughout the system, where the neurotransmitter acetylcholine (ACh) plays a key role in activating ligand-gated ion channels. The cholinergic system is a vital nervous pathway, where cholinergic neurons synthesize, store and release the neurotransmitter ACh. The main receptors that convert the ACh messages are the cholinergic muscarinic acetylcholine receptors, neuronal and muscular nAChRs. When looking back at evolutionary history, ACh is considered to be the oldest transmitter molecule and became present before the nervous cell. In the nervous system cholinergic stimulation mediated through nAChRs controls pathways such as release of transmitters and cell sensitivity, which can influence physiological activity including sleep, anxiety, processing of pain and cognitive functions. nAChRs are cholinergic receptors found in the central nervous system (CNS), peripheral nervous systems (PNS) and skeletal muscles, these receptors are ligand-gated ion channels with binding sites for acetylcholine and other molecules. When ACh or other agonists bind to the receptors it stabilizes the open state of the ion channel allowing influx of cations such as potassium, calcium and sodium ions. The nAChRs are made up by different subunits which determine the quaternary structure of the receptor, those subunits are α subunits (α1−α10), β subunits (β1−β4), one δ subunits, one γ subunit and one ε subunit. nAChRs can be either heteromeric or homomeric. The heteromeric receptors found in the central nervous system are made up by two α subunits and three β subunits with the binding site at the interface of α and the adjacent subunit. These receptors contain two binding sites per receptor and have different affinity for chemicals based on the composition of subunits. Both binding sites work together and thus, both sites need to be occupied with a nAChR agonist so that channel activation can take place. nAChRs containing α2−α6 and β2−β4 subunits have been shown to have higher affinity for ACh than other receptors. Homomeric receptors contain 5 identical subunits, they have 5 binding sites located at the interface between two adjacent subunits. In the year 2000 two homomeric receptors had been identified in humans, the α7 and α8 receptors. There are two binding sites on heteromeric nAChRs; to stabilize the open form of nAChRs, both binding sites must be occupied by agonist, such as nicotine or ACh. The ACh binding site of nAChR is made up by six loops, termed A–F. The A, B and C loops of the binding site are part of the α subunit and are the principal components of the binding site. The adjacent subunit to the α subunit (γ, δ, ε or β) contains the D, E and F loops. α4β2 nAChRs contain two α4 subunits and three β2 subunits, therefore it has two binding sites for ACh and other agonists. α4β2 nAChRs account for approximately 90% of the nAChRs in the human brain and when chronically exposed to nicotine or other nicotine agonists leads to increase in density of α4β2 receptors which is the opposite of what usually happens when other receptors are chronically exposed to their agonists. The α4β2 receptor has been widely studied in regards to Alzheimer's disease as well as for nicotine dependence and in 2009 several drugs are on the market that target the α4β2 nAChR specifically.