nachrs. structure activity relationships for these compounds have been proposed. the optimal pharmacophore of α7 nachr agonist is made of three parts. there is a basic moiety connected to a carbon chain linked to an aromatic moiety by an amide bridge. the amide bridge can be inverted without affecting the potency of the agonist. a biaryl group shows more potency than a monoaryl group as the aromatic moiety and substitution at position 2 on the later aryl group will further increase the potency. potency is higher for agonists with h+ donor/acceptor on the later aryl group on the biaryl group. a high number of hydrogen bond acceptors could decrease permeability across the blood–brain barrier (bbb) due to the polar surface area and needs to be taken into account when designing agonists to target α7 nachrs. various cyclic amine groups can act as the basic moiety and potency stays relatively unchanged for example aryl piperazine, piperidine and morpholine. an acyclic tertiary amine is tolerated as the basic moiety but larger steric groups are less tolerated. many derivatives of quinuclidine such as quinuclidine amide are known to be α7 nachr agonists. sar studies for quinuclidine amide have identified factors that are affecting the potency and affinity of these agonists. para substitution on the quinuclidine ring and the 3-(r) configuration in the stereochemistry is favored. enhanced activity is observed when a 5 membered ring is fused to aromatic moiety. further enhancement is seen when the fused ring is able to supply electron resonance to the amide carbonyl whereas the activity will diminish when the fused ring contains a hydrogen bond donating atom. the rigidity of quinuclidine and the orthogonal orientation of the nitrogen bridge in relations to the amide carbonyl group is presumed important for the optimal binding. the stability of some of the more potent quinuclidine amide derivatives in rat in vitro models have been low however by adding a methyl group to position 2 on the quinuclidine ring the stability has increased greatly. drug development the development of nicotinic acetylcholine receptor agonists began in the early 1990s after the discovery of nicotine's positive effects on animal memory. the development of nicotinic acetylcholine receptor agonists has come a long way since then. nicotinic acetylcholine receptor agonists are gaining increasing attention as drug candidates for multiple central nervous system disorders such as alzheimer's disease, schizophrenia, attention-deficit hyperactivity disorder (adhd) and nicotine addiction. nicotinic acetylcholine receptors are receptors found in the central nervous system, the peripheral nervous systems and skeletal muscles. they are ligand-gated ion channels with binding sites for acetylcholine as well as other agonists. when agonists bind to a receptor it stabilizes the open state of the ion channel allowing influx of cations. in 2009 there were at least five drugs on the market that affect the nicotinic acetylcholine receptors. quinuclidine derivatives quinuclidine carbamates quinuclidine amides quinuclidine ethers products of nicotinic agonist active ingredient product name chemical name pharmaceutical form pharmacodynamic properties therapeutic use structure varenicline tartrate champix, chantix 7,8,9,10-tetrahydro-6,10-methano-6h-pyrazinobenzazepine film coated tablet partial agonist of the nicotinic acetylcholine receptor, subtype α4β2 treatment of tobacco dependence galantamine hydrobromide reminyl, nivalin, razadyne and razadyn er 4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6h-benzofuro-benzazepin-6-ol sustained release capsule, film coated tablet, oral solution cholinesterase inhibitor and a noncompetitive agonist of the nicotinic acetylcholine receptor treatment of dementia caused by alzheimer's disease nicotine nicorette, nicotinell, niquitin, boots nicassist, commit, habitrol, nicoderm cq, nicotrol, thrive 3-pyridine transdermal patch, gum, inhaler, nasal spray, lozenge, microtab, and is naturally found in tobacco agonist of the nicotinic receptor, both ganglion type and α4β2 treatment of tobacco dependence carbachol miostat 2--n,n,n-trimethylethanaminium intraocular solution cholinergic agonist treatment of glaucoma suxamethonium chloride (succinylcholine chloride) anectine, quelicin suxamethonium chloride 2,2'-bis(n,n,n-trimethylethanaminium) intravenous or intramuscular injection depolarizing neuromuscular blocking agent short acting muscle relaxant epibatidine not listed 2-(6-chloropyridin-3-yl)-7-azabicycloheptane not listed agonist of the nicotinic acetylcholine receptor not used as a drug other nicotinic agonists, albeit generally with limited clinical use, include: lobeline, an agonist on ganglion type nicotinic receptors and also affects sensory nerve terminals epibatidine, an agonist on ganglion type, α4β2 and α7 receptors decamethonium causes depolarization block on muscle type receptors, similarly to suxamethonium nicotinic versus muscarinic activity comparison of cholinergic agonists substancereceptor specificityhydrolysis by acetylcholinesterasecomments muscarinicnicotinic choline++++++++essential nutrient acetylcholine+++++++++endogenous ligand carbachol+++++-used in the treatment of glaucoma methacholine++++++ bethanechol+++--used in bladder and gastrointestinal hypotonia. muscarine+++--natural alkaloid found in certain mushrooms. cause of mushroom poisoning nicotine-+++-natural alkaloid found in the tobacco plant. pilocarpine++--used in glaucoma oxotremorine++-- current status currently nicotine receptor agonist research and drug designing is aimed for treatment of multiple diseases and disorders of the cns. targacept has three drug candidates that are in clinical trials; azd3480 (tc-1734) for adhd which is currently in phase ii clinical trials, azd1446 (tc-6683) for alzheimer's disease in collaboration with astrazeneca and tc-5619 for cognitive dysfunctions in schizophrenia. 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. abbott laboratories in partnership with neurosearch have two drug candidates in clinical trials, abt-894, a selective α4β2 nicotine receptor agonist, for adhd and abt-560, a neuronal nicotinic receptor modulator, which was selected by abbott in 2006 as a new development candidate for cognitive dysfunctions. 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.