Nicotinic receptor agonists

Nicotinic Receptor Agonists. There has been significant activity in the development of muscarinic cholinergic receptor agonists for dementia. In addition, agents that interact with nicotinic cholinergic receptors may also have therapeutic value. Nicotinic receptors have been reported to be... 

Galantamine is a cholinesterase inhibitor that also has activity as a nicotinic receptor agonist. 

Decker MW, Majchrzak MJ, Arneric SP. (1993). Effects of lobeline, a nicotinic receptor agonist, on learning and memory. Pharmacol Biochem Behav. 45(3) 571-76. 

Mirza NR, Pei Q, Stolerman IP, Zetterstrom TS. (1996). The nicotinic receptor agonists (—)-nicotine and isoarecolone differ in their effects on dopamine release in the nucleus accumbens. EurJ Pharmacol. Jan. ll 295(2-3) 207-10. 

Wiley JL, James JR, Rosecrans JA (1996) Discriminative stimulus properties of nicotine approaches to evaluating potential nicotinic receptor agonists and antagonists. Drug Dev Res 38 222-230... 

Galantamine is a reversible inhibitor of acetylcholinesterase that also possesses nicotinic receptor agonist properties, and which is used in mild-to-moderate dementia in Alzheimer s disease. 

Martin LF, Kem WR, Freedman R. (2004) a-7 nicotinic receptor agonists Potential new candidates for the treatment of schizophrenia. Psychopharmacology 174 54-64. 

Figure 5. Cartoon of a cholinergic synapse showing major steps in the synthesis of acetylcholine. The two major receptor types, the ionotropic nicotinic receptor and the metabotropic muscarinic receptor, are shown (see also Chapter 1). Presynaptic muscarinic (M2) and nicotinic receptors are also depicted. Drugs which have been widely used to manipulate the cholinergic systems, and which are mentioned in the text, include the muscarinic receptor antagonists scopolamine and atropine and the nicotinic receptor agonist nicotine. Anticholinesterases (discussed elsewhere in this volume) include drugs such as physostigmine, rivastigmine, donepezil, and galanthamine.

Phase 1 is followed by a postdepolarization phase (phase 2) during which only the actions of nicotinic receptor agonists are blocked. This phase takes place after nicotine has acted for several minutes. At this time, the cell partially repolarizes, and its electrical excitabihty returns. The main factor responsible for phase 2 block appears to be desensitization of the receptor to ACh, which causes transmission failure. 

Nomicotine, an organocatalyst studied by Dickerson and co-workers (Entry 5 [52, 58d], Appendix 7.B), reinforces the important principle that even catalysts from Nature can present problems when it comes to toxicity. The family of nicotinic receptor agonists (Figure 7.9) contains several chiral pyrrolidines and piperidines with the potential to act as asymmetric aldol catalysts. Nomicotine, which can be isolated from plants such as tobacco, or readily synthesized by demethylation of the maj or tobacco alkaloid nicotine, was investigated in some depth as an aldol catalyst by Dickerson and Janda in 2002 [52]. 

Figure 7.12 Synthetic nicotinic receptor agonists as potential catalysts.

Nicotinic receptor agonists have been developed in an attempt to further characterize central nervous system cholinergic function and as potential candidates for the treatment of schizophrenia. 

The efficacy of a7-nicotinic receptor agonists has been assessed in multiple animal paradigms of learning and memory. For example, DMXB-A improves monkey performance on a delayed matching to sample task, an effect that persists for 24 h after drug administration (Briggs et al., 1996). DMXB-A... 

Halo-pyridyloxyl- and thioalkylamines derivatives, (IV), prepared by Dull (8) were effective as nicotinic receptor agonists and used in the treatment of Alzheimer s... 

Kihara T, Shimohama S, Akaike A (1999) Effects of nicotinic receptor agonists on beta-amyloid beta-sheet formation. Jpn J Pharmacol 79 393-396 Kihara T, Shimohama S, Sawada H, Honda K, Nakamizo T, Shibasaki H, Kume T, Akaike A (2001) alpha 7 nicotinic receptor transduces signals to phosphatidylinositol 3-kinase to block A beta-amyloid-induced neurotoxicity. J Biol Chem 276 13541-13546 Kihara T, Shimohama S, Urushitani M, Sawada H, Kimura J, Kume T, Maeda T, Akaike A (1998) Stimulation of alpha4beta2 nicotinic acetylcholine receptors inhibits beta-amyloid toxicity. Brain Res 792 331-334... 

Swanson, K.L., Allen, C.N., Aronstam, R.S., Rapoport, H., and Albuquerque, E.X. 1986. Molecular mechanisms of the potent and stereospecific nicotinic receptor agonist (+ )-anatoxin-a. Mol Pharmacol 29, 250-257. 

A wide variety of synthetic processes have been rendered asymmetric through the use of a chiral catalyst. In addition to the types of reaction described above, chiral transition metal catalysts have been used to influence the stereochemical course of isomerization, cyclization, and coupling reactions. As an example, an approach towards the natural product (-)-epibatidine (158) was recently reported by Namyslo and Kaufmann (166). Epibatidine is a potent analgesic and a nicotinic receptor agonist. The synthesis involves an asymmetric Heck-type hydroarylation between the bicyclic alkene (155) and pyridyl iodide (156). A number of bidentate chiral li-... 

Other approaches, some of which are still in clinical development, include restoration of the acetylcholine-dopamine balance in the basal ganglia, neuronal nicotinic receptor agonists, neurotrophic immunophilins, dopamine transport inhibitors, COMT-inhibitors, and adenosine A2A receptor antagonists.162,163 Also surgical therapies are used or under development, including stereotactic thalamotomy, continuous electric thalamus stimulation,164 posteroventral pallidotomy and transplantation of embryonal substantia nigra cells. 

Relief from pain. Selected cholinergic agents have been found that display antinociceptive (analgesic) effects grossly similar to those of morphine. Most of these are nicotinic receptor agonists, but a modest number of muscarinic agonists have been found that also display antinociceptive effects. 

Storch, A. et al., Physostigmine, galanthamine and codeine act as noncompetitive nicotinic receptor agonists on clonal rat pheochromocytoma cells, Eur. J. Pharmacol., 290, 207, 1995. 

I Galantamine. Galantamine is the fourth approved cholinesterase inhibitor, and it also has activity as an allosteric nicotinic receptor agonist. Though galantamine has been shown to be efficacious at dosages... 

Nicolotti, O., PeDegrini-Calace, M., Carrieii, A., Altomare, C., Centeno, N.B., Sanz, E. and Carotti, A. (2001) Neuronal nicotinic receptor agonists a multi-approach development of the pharmacophore. J. Comput. Aid. Mol. Des., 15, 859-872. 

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