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Receptor agonist activity is not a requirement for muscarinic antinociception

The analgesic effects of a series of muscarinic agonists were investigated by use of the mouse acetic acid writhing, gridshock, hot-plate and tail-flick tests. The compounds tested were oxotremorine, pilocarpine, arecoline, aceclidine, RS86 and four 3-3(substituted-1,2,5-thiadiazol-4-yl)- 1,2,5,6-tetrahydro-1-methyl pyridines (substituted TZTP), these being propoxy-TZTP, 3-Cl-propylthio-TZTP, xanomeline (hexyloxy-TZTP) and hexylthio- TZTP. These agonists were also assayed for their ability to displace [3H]oxotremorine-M and [3H]pirenzepine binding and for their functional selectivity at pharmacologic M1, M2 and M3 receptors. These compounds all produced dose-dependent antinociceptive effects in all of the mouse analgesia tests. The effects of oxotremorine in the writhing test were fully antagonized by the muscarinic antagonist scopolamine (0.1 mg/kg), but only partially antagonized by methscopolamine (10 mg/kg) and unaffected by the opioid antagonist naltrexone. 3-Cl-propylthio-TZTP and propoxy-TZTP had virtually no effect at the M1 receptor subtype as measured by the human m1 clone expressed in baby hamster kidney cells or the rabbit vas deferens assay. These compounds, however, were more potent in the analgesia tests than the selective M1 agonists xanomeline and hexylthio-TZTP. These data suggest that muscarinic analgesia is mediated by central muscarinic receptors. However, activity at the M1 receptor subtype is not a requirement for antinociceptive activity.

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Classics in Chemical Neuroscience: Xanomeline

Xanomeline (1) is an orthosteric muscarinic acetylcholine receptor (mAChR) agonist, often referred to as M1/M4-preferring, that received widespread attention for its clinical efficacy in schizophrenia and Alzheimer?s disease (AD) patients. Despite the compound?s promising initial clinical results, dose-limiting side effects limited further clinical development. While xanomeline, and related orthosteric muscarinic agonists, have yet to receive approval from the FDA for the treatment of these CNS disorders, interest in the compound?s unique M1/M4-preferring mechanism of action is ongoing in the field of chemical neuroscience. Specifically, the promising cognitive and behavioral effects of xanomeline in both schizophrenia and AD have spurred a renewed interest in the development of safer muscarinic ligands with improved subtype selectivity for either M1 or M4. This Review will address xanomeline?s overall importance in the field of neuroscience, with a specific focus on its chemical structure and synthesis, pharmacology, drug metabolism and pharmacokinetics (DMPK), and adverse effects.

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Soft drugs. 2. Soft alkylating compounds as potential antitumor agents.

A class of soft alkylating compounds as potential anticancer agents was developed. The first examples include alpha-halo esters of various carboxylic acids. A new method for quantitative evaluation of the alkylating reactivity was developed, using a competitive alkylation reactivity was developed, using a competitive alkylation reaction, followed by NMR analysis of the reaction mixture. The method is sensitive and reproducible. One of the two selected soft alkylating agents, chloromethyl hexanoate, was found to have anticancer activity.

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Aceclidine and pilocarpine interact differently with muscarinic receptor in isolated rabbit iris muscle

The relationship between muscarinic receptor affinity states and the contractile response to the muscarinic agonists carbachol, aceclidine, and pilocarpine, has been examined in the isolated rabbit iris muscle. Contraction of the iris muscle by carbachol and aceclidine was more potent and/or more efficacious than the response to pilocarpine. Analysis of [3H]- Quinuclidinyl benzilate (QNB) binding showed that while both carbachol and aceclidine bound to high- and low-affinity forms of the muscarinic receptor, pilocarpine bound to one affinity state. The efficacy of carbachol and aceclidine to stimulate contraction of the iris muscle was consistent with receptor occupancy theory only when considering the low-affinity state of the muscarinic receptor, and activation of the low-affinity rather than high-affinity binding state of the receptor is likely to mediate the contraction of iris muscle. Therefore, the typical anti-glaucoma muscarinic agonists aceclidine and pilocarpine may interact differently with their target receptors in isolated rabbit iris muscle.

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Optically active 3 – the preparation method of the quinine is mellow (by machine translation)

The invention relates to a method for synthesizing intermediate, which belongs to the field of organic synthesis. In particular to a simple operation, low cost, and is suitable for industrial production of optically active 3 – the preparation method of the quinine is mellow. In order to 4 – piperidine carboxylic acid as the starting material, through esterification, pro-nuclear substituted, Dieckmann condensation, decarboxylation, salt, reduction, acetylation, chemically so as to obtain the intermediate optically active 3 – the quinine is mellow. The above reaction equation is as follows: (by machine translation)

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The cholinergic system and spatial learning

Acetlylcholine (ACh) in the central nervous system is critical for a multitude of functions. Here, we concentrate on declarative memory in humans, and its equivalent episodic-like memory in rodents and highlight current understanding of cholinergic system in these processes. Spatial memory formation represents a simple form of episodic-like memory in rodents that engages the basal forebrain cholinergic system and its target structures. In these, ACh exerts numerous functions. During spatial acquisition learning, ACh efflux into the extracellular space is immediate in hippocampus and cortex; during consolidation of spatial reference memory, ACh levels are low. These requirements explain why ACh receptor blockade during acquisition blocks memory formation, and it is also consonant with the notion that an unspecific enhancement of cholinergic activity during consolidation is detrimental to memory formation. Working and short-term memory for spatial locations engages the nucleus basalis – prefrontal cortex ACh system. ACh activity is trial related and maintained for some time post-training. Striatal cholinergic activity is increased during stimulus-response learning and behavioural flexibility (reversal learning, extinction) providing a possible switch between different behavioural strategies. At present, there is no clear difference between muscarinic and nicotinergic systems with respect to spatial learning. Antagonists of the respective receptors impair memory formation, agonists can reverse these deficits or may, under specific conditions act more like a general cognitive enhancers by way of improving attention. Data reviewed here do not provide conclusive evidence for muscarinic or nicotinic receptors presenting as novel therapeutic targets, and there is no clear indication for ACh derived novel biomarkers for translational medicine.Unresolved and contradictory results are highlighted and discussed.

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Synthesis, biochemical activity and behavioral effects of a series of 1,4,5,6-tetrahydropyrimidines as novel ligands for M1 receptors

A series of novel tetrahydropyrimidines was synthesized and examined for M1 muscarinic receptor activity. 1,4,5,6-tetrahydro-5-methoxycarbonyl-pyrimidine hydrobromide (1a; CDD-0034-C) displayed a high affinity for muscarinic receptors in rat brain and stimulated PI metabolism in rat hippocampus. Compound 1a ameliorated memory deficits associated with lesions of the septohippocampal cholinergic system in rats.

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TREATMENT OF SEXUAL DYSFUNCTION AND FOR IMPROVED SEXUAL QUALITY OF LIFE

Compositions and methods for treating sexual dysfunction and enhancing sexual satisfaction using topical application of alpha-1 adrenergic receptor agonists, muscarinic acetylcholine receptor agonists, nicotinic acetylcholine receptor agonists, and cholinesterase inhibitors are disclosed.

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Influence of the acyl moiety on the hydrolysis of quinuclidinium esters catalyzed by butyrylcholinesterase

Eight chiral esters of quinuclidin-3-ol and butyric, acetic, pivalic and benzoic acid were synthesized as well as their racemic and chiral, quaternary N-benzyl derivatives. All racemic and chiral quaternary compounds were studied as substrates and/or inhibitors of horse serum butyrylcholinesterase (BChE). The best substrate for the enzyme was (R)-N-benzyl butyrate. The rates of hydrolysis decreased in order (R)-butyrate (R)-acetate (7-fold slower) < (R)-pivalate (8-fold slower) < (R)-benzoate (9-fold slower reaction), while (S)-N-benzyl esters were much poorer substrates (320 (butyrate)-4360-fold slower (pivalate) than the appropriate (R)-enantiomer). For all (S)-N-benzyl esters excluding (S)-N-benzyl acetate inhibition constants were determined (Ka = 3.3.60 mumol dm-3). The hydrolysis of racemic mixtures of N-benzyl esters proceeded 1.4 (for acetate)-5.1 (for benzoate) times slower than that of pure (R)-enantiomers of the corresponding concentrations due to the inhibition with (S)-enantiomers. Change of the acyl moiety of the substrate effected both activity and stereoselectivity of the BChE. A reaction mechanism is the microscopic path by which reactants are transformed into products. Each step is an elementary reaction. In my other articles, you can also check out more blogs about Quality Control of Quinuclidin-3-yl acetate Reference£º
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Process for preparing salt of hyaluronic acid with a pharmaceutically active substance

Pharmaceutical preparations for topical administration containing a pharmacologically active substance together with hyaluronic acid or a molecular weight fraction thereof. The hyaluronic acid may be in the form of the free acid or may be a salt with an alkali or alkaline earth metal, magnesium, aluminum or ammonium, or in the form of a salt with one or more pharmacologically active substances.

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