Nicotinic agonist
Examples include nicotine (by definition), acetylcholine (the endogenous agonist of nAChRs), choline, epibatidine, lobeline, varenicline and cytisine.
[4] ABT-418 showed significant increase of delayed matching-to-sample (DMTS) performance in matured macaque apes of different species and sex.
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.
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.
The nAChRs take part in the depolarization of the muscular endplate by increasing cation permeability leading to contraction of skeletal muscles.
Recent investigations have elucidated the structural and Stereochemical elements responsible for the binding capacity and potency of pharmacophore; the presence of a cationic centre and electronegative atoms able to form hydrogen bonds with the center of the pyridine ring in (S)-nicotine confer greater binding affinity, while the (S)-enantiomer is 10-100 times more potent than its (R) conformer.
The azabicyclic ring of epibatidine also affords favorable steric interactions with nAChR receptor, due to its specific internitrogen distance, N+-N, which has been proposed as a significant factor for agonist affinity, however, some debate remains as to its influence.
Contemporary theories suggest a 7-8 Å difference between points complementing the protonated nitrogen atom and hydrogen-bond acceptor could enhance potency.
Recent research has focussed on the α7 and α4β2 receptor subtypes for the development of drugs to treat nicotine dependence and cognitive impairment, such as Alzheimer's disease.
By using a model for the nAChR muscle receptor subtype (α1)2β1δγ, the following results were obtained: where anatoxin had the highest activity efficacy, and tubocurare the lowest.
These results suggest anatoxin derivatives could be improve understanding of structure-activity relationships (SAR) for muscle nAChRs.
[23] Combining the structural elements of ACh and nicotine, thus reducing conformational flexibility with a cyclopropane ring, has led to the discovery of potent and selective α4β2 nAChR ligands.
Modulation of three structural elements - the linker, and substitution of either the amino group or pyridine ring - can be used to determine the influence of ligands on potency and selectivity.
Higher numbers of hydrogen bond acceptors likely decrease permeability across the blood–brain barrier (BBB) due to the polar surface area, and need to be taken into account when designing agonists targeting α7 nAChRs.
[15] Various cyclic amine groups - for example aryl piperazine, piperidine and morpholine - can be used as the basic moiety, while having limited affect on agonist potency.
Acyclic tertiary amines are well sufficient as basic moieties, however larger groups negatively affect tolerability due to their sterics.
The rigidity of quinuclidine and orthogonality of the nitrogen bridge relative to the amide carbonyl has been proposed as important for optimal binding.
Memory pharmaceuticals with its partner Roche has one drug candidate, MEM 3454 (RG3487), a partial agonist of the nicotinic α7 receptor, for Alzheimer's disease.
[42] EnVivo pharmaceuticals has one drug candidate in clinical trials, EVP-6124, a selective α7 nicotine receptor agonist for Alzheimer's disease and schizophrenia and one follow-up compound, EVP-4473, that has successfully completed pre-clinical development.
