Muscarinic Ml agonists

Fig. 12.10 Distributions of three large GPCR-specific ligand groups within the Kohonen map (a) Tachykinin NKl antagonists (1400 compounds), (b) Muscarinic Ml agonists (553 compounds), (c), 63-Adrenoceptor agonists (433 compounds).

From a study (15) of a series of muscarinic Ml agonists derived from the structure of arecoline (16) and typified by (17), it was con-... 

Nitsch RM, Deng M, Tennis M, Schoenfeld D, Growdon JH. 2000. The selective muscarinic Ml agonist AF102B decreases levels of total A beta in cerebrospinal fluid of patients with Alzheimer s disease. Ann. Neurol. 48 913-18... 

FIGURE 6.11 Progressive passage from minaprine to a potent and selective partial muscarinic Ml agonist. ... 

Velazquez-Moctezuma, J., Gillin, J. C. Shiromani, P. J. (1989). Effect of specific Ml, M2 muscarinic receptor agonists on REM sleep generation. Brain Res. 503, 128-31. 

Although ibogaine binds to muscarinic Ml and M2 receptors in the micromolar range, its action there is uncertain (Sweetnam et al. 1995). It fails to alter the adenylyl cyclase activity of a muscarinic agonist carbachol (Rabin and Winter 1996b). 

Sanchez C, Arnt J, Didriksen M, Dragsted N, Lenz SM, Matz J (1998) In vivo muscarinic cholinergic mediated effects of Lu 25-109, a Ml agonist and M2/M3 antagonist in vitro. Psychopharmacology 137 233-240... 

The performance of this LC/MS/MS quantitative analysis was demonstrated on a selective muscarinic Ml receptor partial agonist, SR 46559, which was under clinical development for the potential symptomatic treatment of the cognitive disorders associated with Alzheimer s disease. The full-scan mass spectrum and the corresponding product ion spectrum are shown in Figure 6.40. The m/z 268 product ion is identified along with the [M+H]+ ion at m/z 341 for the SRM experiment. Also, the m/z 273 product ion and m/z 346 [M+H]+ ion from the corresponding internal standard, 2H5-SR 46559, are identified for SRM. 

FIGURE 19.16 The mutagenicity of the original dimethylenic muscarinic Ml partial agonist could be abolished in changing the dimethylene to a trimethylene side chain. 

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. 

All muscarinic receptors are members of the seven transmembrane domain, G protein-coupled receptors, and they are structurally and functionally unrelated to nicotinic ACh receptors. Activation of muscarinic receptors by an agonist triggers the release of an intracellular G-protein complex that can specifically activate one or more signal transduction pathways. Fortunately, the cellular responses elicited by odd- versus even-numbered receptor subtypes can be conveniently distinguished. Activation of Ml, M3, and M5 receptors produces an inosine triphosphate (IP3) mediated release of intracellular calcium, the release of diacylglyc-erol (which can activate protein kinase C), and stimulation of adenylyl cyclase. These receptors are primarily responsible for activating calcium-dependent responses, such as secretion by glands and the contraction of smooth muscle. 

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