Muscarinic Mj receptor

The formation of numerous ring-substituted spirolactams (53b) employed this methodology, which to date has also found application in a number of natural product syntheses. For example, the critical spirane junction-forming step in the synthesis of the muscarinic Mj receptor antagonist (—)-TAN1251A (58) from L-tyrosine involves PIFA-induced cyclization of the hydroxamic ester 56 to 57 according to Scheme 12 °. 

O Kane EM, Stone TW (1998) Interaction between adenosine Ai and A2 receptor-mediated responses in the rat hippocampus in vitro. Eur J Pharmacol 362 17-25 Ohkubo S, Kimura J, Matsuoka I (2000) Ecto-alkaline phosphatase in NG108-15 cells a key enzyme mediating PI antagonist sensitive ATP response. Br J Pharmacol 131 1667-2 Okada M, Mizuno K, Kaneko S (1996) Adenosine Ai and A2 receptors modulate extracellular dopamine levels in rat striatum. Neurosci Lett 212 53-6 Okada M, Nutt DJ, Murakami T et al (2001) Adenosine receptor subtypes modulate two major functional pathways for hippocampal serotonin release. J Neurosci 21 628 40 Oliveira L, Correia-de-Sd P (2005) Protein kinase A and Cavl (L-Type) channels are common targets to facilitatory adenosine A2a and muscarinic Mj receptors on rat motoneurons. Neurosignals 14 262-72... 

Receptor affinities of metabolites may variably contribute to the in-vivo or clinical action. For example, the olanzapine metabolite 2-hydroxmethyl-olanzapine has affinity to histamine Hj and adrenergic alpha-1 receptors comparable to that of the parent compound [58]. Further, N-desmethylclozapine, the main metabolite of clozapine, has remarkable agonism at muscarinic Mj receptors [59], and it is hypothesized that this action may greatly contribute to the uniquely beneficial clinical profile of clozapine [60]. 

Another example is the antidepressant minaprine (Figure 6.11). In addition to reinforcing serotoninergic and dopaminergic transmission, this amino-pyridazine possesses weak afhnity for muscarinic Mj receptors (A = I7 iM). Simple chemical variations allowed to abolish the dopaminergic and serotoninergic activities and to boost the cholinergic activity up to nanomolar concentrations. " ... 

To test the specificity of PPADS, we compared its blocking activity on P2-purinoceptor-mediated responses with its effects on responses mediated by a -adrenoceptors in rat vas deferens, histamine H]-receptors and muscarinic M3-receptors in guinea-pig ileum, adenosine A j-receptors and muscarinic M2-receptors in guinea-pig atria and adenosine A2-receptors and muscarinic Mj-receptors in rat duodenum. PPADS (100 pM) had no significant effect on either the potency or maximum responses to the respective agonists used in the various receptor preparations. These results demonstrate that the antagonistic effects of PPADS against purine-nucleotides at P2-purinoceptors are specific. 

Larson, Soncrant, 1994), did not stimulate PLA j-related uptake of [9,10- H Ipalinilale. Autoradiography confirmed that increased incorporation occurred at sites of muscarinic Mj receptors, particularly within the neocortex (Fig. 5). Taken together, the data indicate that arecoline activated PL A -medialed release of arachidonate at M i synapses, independently of changes in cerebral blood flow. 

The goal of the investigations, presented here, was to optimize the affinity of the modulators for the common allosteric binding site of muscarinic Mj receptors, the orthosteric site of which was liganded with the antagonist A -methylscolopamine. The phthalimido substituted alkane-bisammonium compound W84 (Fig. 1) was taken as a starting point. 

E., Mohr, K., 1999. Structure-activity relationships in a series of bisquaternary phthalimidine derivatives modulating the muscarinic Mj-receptor allosterically. J. Med. Chem., submitted. 

Fig. 1. Schematic representation of the wild-type human Mj and rat Mj receptors, the Mj-trunc and Mj-tail fragments, and the mutants Mj-short and MjfAsndCM Ser) muscarinic receptors. The truncated fragment, M2-trunc, contains the amino-terminal domain, the first five hydrophobic transmembrane regions and the initial portion (56 amino acids) of the third cytoplasmic (i3) loop of the wild-type muscarinic Mj receptor. The M3-tail fragment contains the final portion of the i3 loop (105 amino acids), the last two hydrophobic transmembrane regions and the carboxyl-terminal segment of the wild-type M3 muscarinic receptor. The short construct (Mj-short) represents a receptor in which 196 amino acids of the i3 loop have been deleted the remaining loop is 43 amino acids long. The point mutant MjfAsndOd -> Ser) has the asparagine 404 replaced with serine. The amino acid differences in the transmembrane domains VI and VII of the human muscarinic M2 and the rat muscarinic M3 receptors are presented.

Delta opioid receptor Dopamine D2 receptor GABAg receptor Muscarinic Mj receptor Substance P receptor... 

Methacholine acts through muscarinic (Mj) receptors to contract smooth muscle. It is often aerosolized and delivered in increasing concentrations during bron-choprovocation challenge. Asthma patients typically respond to inhaled methacholine at lower doses than do subjects who do not have asthma. Thus, it is often used to differentiate between asthmatic patients and non asthmatic subjects. It is also used to determine the effectiveness of inhaled medications that act to pre-... 

Muscarinic Mj receptor CNS, CV, GI Vagal effects, blood pressure changes, decrease gastric acid secretion... 

A natural hyoscyamine analogue with structural similarities to atropine though reduced flexibihty in the acyl moiety, bonabihne A, has been isolated from a con-volvulaceous twining shrub, Bonamia spectabilis (Ott et al. 2006). This metabolite has shown remarkable muscarinic (Mj) receptor antagonist activity (pA value 6.65... 

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