Muscarinics

Muscarine is a poisonous substance present in the mushroom Amanita muscana Its struc ture IS represented by the constitution shown here... 

Several cholinergic strategies, other than cholinesterase inhibition, have been employed with the intention of ameliora ting the symptoms of AD. These include precursor loading acetylcholine release enhancement, and direct activation of both muscarinic and nicotinic receptors. 

The anainoacridines, tacrine (19) and its 1-hydroxy metaboUte, velnacrine (20), are reversible inhibitors of AChE. Tacrine was synthesi2ed in the 1940s and has been used clinically for the treatment of myasthenia gravis and tardive dyskinesia (115). Placebo-controUed studies have indicated modest efficacy of tacrine to treat AD dementia (122,123) and in 1993 the dmg was recommended for approval by the PDA under the trade name Cognex. Tacrine (19) has been shown to interact with sites other than AChE, such as potassium channels (124) and muscarinic receptors. However, these interactions are comparatively weak and are not thought to contribute to the biological activity of the dmg at therapeutic levels (115). 

Initial attempts to treat AD using direct cholinergic agonists were limited by low efficacy and side-effect issues (140—142). Thus trials using RS-86 (25), oxotremorine [70-22-4] (26), arecoline [63-75-2] (27), and pilocarpine [92-32-7] (28) to treat AD were equivocal (Eig. 5). However, the identification of multiple subtypes of muscarinic receptors has stimulated a search for subtype specific muscarinic agonists which may limit side effects while increasing efficacy. 

CI-979 (29) is a balanced muscarinic agonist having equal affinities for cloned ml and m2 receptors (144). However, unlike prototypical muscarinic compounds such as (25), (29) increases central muscarinic tone, as indicated by behavioral and electroencephalogram (EEG) parameters, at doses lower than those requited to produce gastrointestinal effects (144). CI-979 is well tolerated in humans up to a dose of 1 mg. Dose-limiting side effects such as stomach pain and emesis were observed at a dose of 2 mg. 

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... 

Acetylcholine. Acetylcholiae (ACh) (1) is a crystalliae material that is very soluble ia water and alcohol. ACh, synthesized by the enzyme choline acetyltransferase (3), iateracts with two main classes of receptor ia mammals muscarinic (mAChR), defiaed oa the basis of the agonist activity of the alkaloid muscarine (4), and nicotinic (nAChR), based on the agonist activity of nicotine (5) (Table 1). m AChRs are GPCRs (21) n AChRs are LGICs (22). 

Acetyl choline is the natural neurotransmitter for the cholinergic receptor. Two distinct receptor subtypes have been characterized based on their binding affinity for either nicotine (189) and (190) or muscarine (191). 

Fig. 9. Correlation between binding and pharmacologic affinities where the dashed lines correspond to the theoretical correlation of 1 1 for a series of muscarinic receptor (a) antagonists, (1)—(9) and (b) agonists, (10)—(19). Correlation for the antagonists is essentially 1 1, deviating markedly from that...

Table 4. Structures of Muscarinic Receptor Antagonists and Agonists...

A critical component of the G-protein effector cascade is the hydrolysis of GTP by the activated a-subunit (GTPase). This provides not only a component of the amplification process of the G-protein cascade (63) but also serves to provide further measures of dmg efficacy. Additionally, the scheme of Figure 10 indicates that the coupling process also depends on the stoichiometry of receptors and G-proteins. A reduction in receptor number should diminish the efficacy of coupling and thus reduce dmg efficacy. This is seen in Figure 11, which indicates that the abiUty of the muscarinic dmg carbachol [51 -83-2] to inhibit cAMP formation and to stimulate inositol triphosphate, IP, formation yields different dose—response curves, and that after receptor removal by irreversible alkylation, carbachol becomes a partial agonist (68). 

General types of physiological functions attributed to quaternary ammonium compounds are curare action, muscarinic—nicotinic action, and ganglia blocking action. The active substance of curare is a quaternary that can produce muscular paralysis without affecting the central nervous system or the heart. Muscarinic action is the stimulation of smooth-muscle tissue. Nicotinic action is primary transient stimulation and secondary persistent depression of sympathetic and parasympathetic ganglia. 

DP Mamott, IG Dougall, P Meghani, Y-J Liu, DR Flower. Lead generation using pharmacophore mapping and three-dimensional database searching Application to muscarinic M3 receptor antagonists. J Med Chem 42 3210-3216, 1999. 

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