scispace - formally typeset
Search or ask a question
Author

Masahiko Sugimoto

Bio: Masahiko Sugimoto is an academic researcher. The author has contributed to research in topics: Muscarinic acetylcholine receptor & Muscarinic acetylcholine receptor M3. The author has an hindex of 4, co-authored 7 publications receiving 215 citations.

Papers
More filters
Journal Article
TL;DR: Functional studies confirm that brucine analogs are allosteric enhancers of ACh affinity at certain muscarinic receptor subtypes.
Abstract: In radioligand binding studies, it has been reported that brucine, N-chloromethyl brucine, and brucine N-oxide increased the affinity of acetylcholine for M1, M3, and M4 muscarinic receptors, respectively, in a manner consistent with the predictions of the ternary complex allosteric model. We now demonstrate an equivalent ability of these three allosteric agents to modulate the actions of acetylcholine in functional studies in membranes and in whole cells. The enhancing actions of brucine and brucine N-oxide on acetylcholine (ACh) potency at M1 and M4 receptors respectively have been confirmed in guanosine-5'-O-(3-[35S]thio)triphosphate, GTPase, cAMP, and intracellular Ca2+ mobilization assays of function. In general, neither the basal nor the maximally stimulated response to ACh is affected. The subtype-selective allosteric effects of N-chloromethyl brucine on M2 and M3 receptors were shown to be qualitatively and quantitatively the same in guanosine-5'-O-(3-[35S]thio)triphosphate functional assays, in terms of both its affinity and cooperativity with ACh, as those found in binding assays. Neutral cooperativity of N-chloromethyl brucine with ACh on M4 receptor function was also observed, thereby demonstrating its "absolute subtype selectivity": a lack of action at any concentration at M4 receptors and an action at M2 and M3 receptors. The enhancing action of N-chloromethyl brucine on neurogenically released ACh binding at M3 receptors was also detected in whole tissue as an increased contraction of the isolated guinea pig ileum to submaximal electrical stimulation. In conclusion, these functional studies confirm that brucine analogs are allosteric enhancers of ACh affinity at certain muscarinic receptor subtypes.

96 citations

Journal ArticleDOI
TL;DR: Muscarinic agents may act only on a single muscarinic receptor subtype which is functioning sub-optimally and therefore be of use therapeutically in the early stages of Alzheimer's Disease.

61 citations

Patent
27 Jul 1995
TL;DR: In this paper, the same or different compounds of formula (Ib) are defined for allosteric effectors at muscarinic receptors, which are useful in the treatment and prophylaxis of disorders associated with muscarinea receptors.
Abstract: Compounds of formula (I) wherein Z represents a methylene group, a methine group, a group of formula ⊃NH or a group of formula ⊃N-, and W represents a methylene group, a methine group, a sulfur atom or a group of formula νS→(O)v, where v is 1 or 2; is a single or double bond; at least one of Y?1, Y2, Y3 and Y4? represents a carboxyl group, a sulfonamide group or a group of formula -(A)?p-B?1-T1, wherein A is S or O, T1 is a carboxyl group, a thiocarboxy group, a dithiocarboxy group, a sulfonamide group or a tetrazolyl group, B1 is a bond, an optionally substituted alkylene group and p is 0 or 1; the rest of Y?1, Y2, Y3 and Y4? are the same or different and are H, halogen, nitro, OH, SH, NH?2?, optionally substituted alkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, aryl, aralkyloxy, aralkylthio and Y?1 + Y2? may together be a lactone or keto; one of R?1 and R2? is H, alkyl, alkanoyl, aryl, arylcarbonyl, aralkyl, carboxyl, sulfonamide or a group of formula -(O)?q-B?2-T2, wherein T2 is COOH, sulfonamide or tetrazolyl, B2 is an optionally substituted alkylene, and q is 0 or 1; the other of R?1 and R2? is H, alkyl, aryl or aralkyl, or R?1 and R2? together represent a group of formula (Ib'), wherein [R?10, R11 and R12? are the same or different and each is H, OH, halogen, haloalkyl, optionally substituted alkyl, alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl]; R3 is H or an amino protecting group; and pharmaceutically acceptable salts and esters thereof are allosteric effectors at muscarinic receptors, and are useful in the treatment and prophylaxis of disorders associated with muscarinic receptors

37 citations

Journal ArticleDOI
TL;DR: These results provide the first well characterised instance of a positive enhancer of ACh at M2 receptors, and illustrate the difficulty of predicting such an effect.

18 citations


Cited by
More filters
Journal Article
TL;DR: Actions of acetylcholine in the periphery are the result of activation of either the ionotropic nicotinic receptor or the metabotropic muscarinic receptor, in the mammalian central nervous system (CNS)c.
Abstract: Actions of acetylcholine in the periphery are the result of activation of either the ionotropic nicotinic receptor or the metabotropic muscarinic receptor. In the mammalian central nervous system (CNS)c, both nicotinic and muscarinic receptor subtypes are present on neurons, although there is as yet

1,445 citations

Journal ArticleDOI
TL;DR: There have been tremendous advances in the discovery of novel ligands for GPCRs that act at allosteric sites to regulate receptor function that provide high selectivity, novel modes of efficacy and may lead to novel therapeutic agents for the treatment of multiple psychiatric and neurological human disorders.
Abstract: Despite G-protein-coupled receptors (GPCRs) being among the most fruitful targets for marketed drugs, intense discovery efforts for several GPCR subtypes have failed to deliver selective drug candidates. Historically, drug discovery programmes for GPCR ligands have been dominated by efforts to develop agonists and antagonists that act at orthosteric sites for endogenous ligands. However, in recent years, there have been tremendous advances in the discovery of novel ligands for GPCRs that act at allosteric sites to regulate receptor function. These compounds provide high selectivity, novel modes of efficacy and may lead to novel therapeutic agents for the treatment of multiple psychiatric and neurological human disorders.

989 citations

Journal ArticleDOI
TL;DR: Allosteric modulators could offer several advantages over orthosteric ligands, including greater selectivity and saturability of their effect.
Abstract: Cell-surface receptors are the targets for more than 60% of current drugs. Traditionally, optimizing the interaction of lead molecules with the binding site for the endogenous agonist (orthosteric site) has been viewed as the best means of achieving selectivity of action. However, recent developments have highlighted the fact that drugs can interact with binding sites on the receptor molecule that are distinct from the orthosteric site, known as allosteric sites. Allosteric modulators could offer several advantages over orthosteric ligands, including greater selectivity and saturability of their effect.

664 citations

Journal ArticleDOI
TL;DR: A comprehensive review of pharmacological and medical aspects of the muscarinic class of acetylcholine agonists and antagonists is presented and the therapeutic benefits of achieving receptor subtype selectivity are outlined.
Abstract: A comprehensive review of pharmacological and medical aspects of the muscarinic class of acetylcholine agonists and antagonists is presented. The therapeutic benefits of achieving receptor subtype selectivity are outlined and applications in the treatment of Alzheimer’s disease are discussed. A selection of chemical routes are described, which illustrate contemporary methodology for the synthesis of chiral medicinal compounds (asymmetric synthesis, chiral pool, enzymes). Routes to bicyclic intrannular amines and intramolecular Diels-Alder reactions are highlighted.

491 citations

Journal ArticleDOI
TL;DR: Criteria that must be met during design of ligand-targeted drugs (LTDs) to achieve the required therapeutic potency with minimal toxicity are summarized.
Abstract: Safety and efficacy constitute the major criteria governing regulatory approval of any new drug. The best method to maximize safety and efficacy is to deliver a proven therapeutic agent with a targeting ligand that exhibits little affinity for healthy cells but high affinity for pathologic cells. The probability of regulatory approval can conceivably be further enhanced by exploiting the same targeting ligand, conjugated to an imaging agent, to select patients whose diseased tissues display sufficient targeted receptors for therapeutic efficacy. The focus of this Review is to summarize criteria that must be met during design of ligand-targeted drugs (LTDs) to achieve the required therapeutic potency with minimal toxicity. Because most LTDs are composed of a targeting ligand (e.g., organic molecule, aptamer, protein scaffold, or antibody), spacer, cleavable linker, and therapeutic warhead, criteria for successful design of each component will be described. Moreover, because obstacles to successful drug design can differ among human pathologies, limitations to drug delivery imposed by the unique characteristics of different diseases will be considered. With the explosion of genomic and transcriptomic data providing an ever-expanding selection of disease-specific targets, and with tools for high-throughput chemistry offering an escalating diversity of warheads, opportunities for innovating safe and effective LTDs has never been greater.

367 citations