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Abraham Fisher - One of the best experts on this subject based on the ideXlab platform.
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cholinergic modulation of amyloid precursor protein processing with emphasis on m1 Muscarinic receptor perspectives and challenges in treatment of alzheimer s disease
Journal of Neurochemistry, 2012Co-Authors: Abraham FisherAbstract:J. Neurochem. (2012) 120 (Suppl. 1), 22–33. Abstract The prescribed drugs for treatment of cognitive deficits in Alzheimer’s disease (AD) patients are regarded as symptomatic drugs. Effective disease modifying therapies are not yet prescribed in AD patients. Three major hallmarks of AD (e.g. cholinergic hypofunction, Aβ and tau neuropathologies) are closely linked raising the expectation that restoring the cholinergic hypofunction to normal, in particular via selective activation of M1 Muscarinic receptors, may alter the onset or progression of AD dementia. This review is focused mainly on modulation of amyloid precursor processing and Aβ levels in the brain via cholinergic treatment strategies based on M1 Muscarinic Agonists versus other cholinergic treatments (e.g. cholinesterase inhibitors prescribed for treatment of AD, M2 antAgonists and nicotinic Agonists). Advantages and potential drawbacks of these treatment modalities are reviewed versus the notion that due to an elusive etiology of AD, future disease modifiers should address comprehensively most of these AD hallmarks (e.g. Aβ pathology, tau and tangle pathologies, as well as the cholinergic hypofunction and cognitive impairments). This major requirement may be fulfilled with M1-selective Muscarinic Agonists and less with other reviewed cholinergic treatments.
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cholinergic treatments with emphasis on m1 Muscarinic Agonists as potential disease modifying agents for alzheimer s disease
Neurotherapeutics, 2008Co-Authors: Abraham FisherAbstract:The only prescribed drugs for treatment of Alzheimer’s disease (AD) are acetylcholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine, and tacrine) and memantine, an NMDA antagonist. These drugs ameliorate mainly the symptoms of AD, such as cognitive impairments, rather than halting or preventing the causal neuropathology. There is currently no cure for AD and there is no way to stop its progression, yet there are numerous therapeutic approaches directed against various pathological hallmarks of AD that are extensively being pursued. In this context, the three major hallmark characteristics of AD (i.e., the CNS cholinergic hypofunction, formation of β-amyloid plaques, and tangles containing hyperphosphorylated tau proteins) are apparently linked. Such linkages may have therapeutic implications, and this review is an attempt to analyze these versus the advantages and drawbacks of some cholinergic compounds, such as acetylcholinesterase inhibitors, M1 Muscarinic Agonists, M2 antAgonists, and nicotinic Agonists. Among the reviewed treatments, M1 selective Agonists emerge, in particular, as potential disease modifiers.
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M1 Muscarinic Agonists target major hallmarks of Alzheimer's disease--the pivotal role of brain M1 receptors.
Neuro-degenerative diseases, 2008Co-Authors: Abraham FisherAbstract:The M1 Muscarinic receptor (M1 mAChR) is a therapeutic target in Alzheimer’s disease (AD) and the M1-selective Muscarinic Agonists AF102B, AF150(S) and AF267B are cognitive enhancers and potential dis
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M1 Muscarinic Agonists target major hallmarks of Alzheimer's disease--an update.
Current Alzheimer research, 2007Co-Authors: Abraham FisherAbstract:UNLABELLED The M1 Muscarinic receptor (M1 mAChR), preserved in Alzheimer's disease (AD), is a pivotal target that links major hallmarks of AD, e.g. cholinergic deficiency, cognitive dysfunctions, beta-amyloid (Abeta) and tau pathologies. Some Muscarinic Agonists, while effective in AD, had limited clinical value due to adverse effects and lack of M1 selectivity. The M1 selective Muscarinic Agonists AF102B [Cevimeline], AF150(S) and AF267B - i) elevated alphaAPPs, decreased Abeta levels and tau hyperphosphorylation, and blocked Abeta-induced neurotoxicity, in vitro, via M1 mAChR-modulation of kinases (e.g. PKC, MAPK and GSK3beta); ii) restored cognitive deficits, cholinergic markers, and decreased tau hyperphosphorylation in relevant models with a wide safety margin. AF267B decreased brain Abeta levels in hypercholesterolemic rabbits and decreased CSF Abeta42 in rabbits and removed vascular Abeta42 deposition from cortex in cholinotoxin-treated rabbits. In 3x transgenic-AD mice that recapitulate the major pathologies and cognitive deficits of AD, chronic AF267B treatment rescued cognitive deficits and decreased Abeta42 and tau pathologies in the cortex and hippocampus (not amygdala), via M1 mAChR-activation of ADAM17/TACE and decreased BACE1 steady state levels and inhibition of GSK3beta, extending findings from above. CONCLUSIONS A comprehensive therapy should target all AD hallmarks, regardless of the culprit(s) responsible for the disease. In this context, AF267B is the 1(st) reported low MW CNS-penetrable mono-therapy that meets this challenge. Clinical trials will determine if AF267B may become an important therapy in AD.
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m1 Muscarinic Agonists can modulate some of the hallmarks in alzheimer s disease implications in future therapy
Journal of Molecular Neuroscience, 2003Co-Authors: Abraham Fisher, Michal Kligerspatz, Niva Natan, Hagar Sonego, Itzhak Marcovitch, Zipora Pittel, Rachel Haring, Nira Barner, Inbal Egozi, Rachel BrandeisAbstract:M1 Muscarinic receptors (M1 mAChRs) play a role in an apparent linkage of three major hallmarks of Alzheimer's disease (AD): beta-amyloid (Abeta) peptide; tau hyperphosphorylation and paired helical filaments (PHFs); and loss of cholinergic function conducive to cognitive impairments. We evaluated the M1 Muscarinic Agonists AF102B (Cevimeline, EVOXAC trade mark : prescribed for Sjogren's syndrome), AF150(S), and AF267B on some of these hallmarks of AD. Activation of M1 mAChRs with these Agonists leads, inter alia, to enhanced secretion of amyloid precursor protein (alpha-APP), (via alpha-secretase activation), to decreased Abeta (via gamma-secretase inhibition), and to inhibition of Abeta- and/or oxidative stress-induced cell death. In several animal models mimicking different aspects of AD, these drugs restored cognitive impairments, and in select cases induced a decrease in brain Abeta elevation, with a high safety margin, following po administration. Notably, in mice with small hippocampi, unlike rivastigmine and nicotine, AF150(S) and AF267B restored cognitive impairments also on escape latency in a Morris water maze paradigm, in reversal learning. Studies from other labs showed that AF102B and talsaclidine (another M1 agonist) decreased cerbrospinal fluid (CSF) Abeta in AD patients following chronic treatment, being the first reported drugs with such a profile. The clinical significance of these studies remains to be elucidated, yet based on in vivo (rabbits) and in vitro studies (cell cultures), our M1 Agonists can decrease brain Abeta, owing to a novel and dual complementary effect (e.g., inhibition of gamma-secretase and activation of alpha-secretase). Remarkably, although M1 Agonists can decrease CSF Abeta in AD patients, an increased AD-type pathology in Parkinson's disease was recently been associated with chronic antiMuscarinic treatment. In another aspect, these Agonists decreased tau hyperphosphorylation in vitro and in vivo. Notably, nicotinic Agonists or cholinesterase inhibitors increased tau hyperphosphorylation. In summary, the M1 Agonists tested are effective on cognition and behavior and show unique disease-modifying properties owing to beneficial effects on major hallmarks of AD. This may place such drugs in the first line of modern AD therapies (e.g., beta- or gamma-secretase inhibitors, vaccines against Abeta, statins, and inhibitors of tau hyperphosphorylation).
Barry Sidney Orlek - One of the best experts on this subject based on the ideXlab platform.
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design of r z α methoxyimino 1 azabicyclo 2 2 2 octane 3 acetonitrile sb 202026 a functionally selective azabicyclic Muscarinic m1 agonist incorporating the n methoxy imidoyl nitrile group as a novel ester bioisostere
Journal of Medicinal Chemistry, 1997Co-Authors: Steven Mark Bromidge, Frank Brown, Frederick Cassidy, Michael S G Clark, Steven Dabbs, Michael S Hadley, Julie Hawkins, Loudon Julia Mary, Christopher B Naylor, Barry Sidney OrlekAbstract:Loss of cholinergic function is believed to be implicated in the cognitive decline associated with senile dementia of the Alzheimer type (SDAT). The disease is characterized by progressive loss of Muscarinic receptors located on nerve terminals while postsynaptic Muscarinic M1 receptors appear to remain largely intact. Muscarinic Agonists acting directly on postsynaptic receptors offer the prospect of countering the cholinergic deficit in SDAT. This study describes a novel series of azabicyclic Muscarinic Agonists, which incorporate an oxime ether or modified oxime ether group as an ester bioisostere. Modification of the oxime ether function by the introduction of electron withdrawing groups led to the finding that the (Z)-N-methoxy imidoyl nitrile group serves as a stable methyl ester bioisostere. This culminated in the discovery of the quinuclidinyl N-methoxy imidoyl nitrile R-(+)-(Z)-5g which is a functionally selective Muscarinic M1 partial agonist currently in phase III clinical trials for the treatment of SDAT. The selective profile of R-(+)-(Z)-5g can be rationalized in terms of the relative affinity of the compound at Muscarinic receptor subtypes, the degree of agonist efficacy, and brain penetrancy.
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design of r z alpha methoxyimino 1 azabicyclo 2 2 2 octane 3 acetonitri le sb 202026 a functionally selective azabicyclic Muscarinic m1 agonist incorporating the n methoxy imidoyl nitrile group as a novel ester bioisostere
Journal of Medicinal Chemistry, 1997Co-Authors: Steven Mark Bromidge, Frank Brown, Frederick Cassidy, Michael S G Clark, Steven Dabbs, Michael S Hadley, Julie Hawkins, Loudon Julia Mary, Christopher B Naylor, Barry Sidney OrlekAbstract:Loss of cholinergic function is believed to be implicated in the cognitive decline associated with senile dementia of the Alzheimer type (SDAT). The disease is characterized by progressive loss of Muscarinic receptors located on nerve terminals while postsynaptic Muscarinic M1 receptors appear to remain largely intact. Muscarinic Agonists acting directly on postsynaptic receptors offer the prospect of countering the cholinergic deficit in SDAT. This study describes a novel series of azabicyclic Muscarinic Agonists, which incorporate an oxime ether or modified oxime ether group as an ester bioisostere. Modification of the oxime ether function by the introduction of electron withdrawing groups led to the finding that the (Z)-N-methoxy imidoyl nitrile group serves as a stable methyl ester bioisostere. This culminated in the discovery of the quinuclidinyl N-methoxy imidoyl nitrile R-(+)-(Z)-5g which is a functionally selective Muscarinic M1 partial agonist currently in phase III clinical trials for the treatment of SDAT. The selective profile of R-(+)-(Z)-5g can be rationalized in terms of the relative affinity of the compound at Muscarinic receptor subtypes, the degree of agonist efficacy, and brain penetrancy.
William S. Messer - One of the best experts on this subject based on the ideXlab platform.
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synthesis and biological characterization of 1 methyl 1 2 5 6 tetrahydropyridyl 1 2 5 thiadiazole derivatives as Muscarinic Agonists for the treatment of neurological disorders
Journal of Medicinal Chemistry, 2003Co-Authors: Yang Cao, Minjia Zhang, Selina Lee, Mary Elizabeth Wroblewski, Trisha Whipple, Peter I Nagy, Krisztina Takacsnovak, Attila Balazs, Szilard Toros, William S. MesserAbstract:Muscarinic Agonists might be useful in the treatment of neurological disorders, including Alzheimer's disease, schizophrenia, chronic pain, and drug abuse. Previous studies identified a series of bis-1,2,5-thiadiazole derivatives of 1,2,5,6-tetrahydropyridine with high activity and selectivity for Muscarinic receptors. To develop compounds with improved central nervous system penetration, several new derivatives were synthesized and characterized for Muscarinic receptor binding and activity. One ligand (11) exhibited agonist activity at M 1 , M 2 , and M 4 receptors, a selectivity profile suggesting potential utility in the treatment of schizophrenia.
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The utility of Muscarinic Agonists in the treatment of Alzheimer's disease.
Journal of Molecular Neuroscience, 2002Co-Authors: William S. MesserAbstract:Alzheimer’s disease is a progressive neurological disorder characterized by amyloid plaques and neurofibrillary tangles along with memory and cognitive deficits associated with a loss of basal forebrain cholinergic neurons. Efforts to treat Alzheimer’s disease have focused on compounds that elevate cholinergic activity such as cholinesterase inhibitors and direct acting Muscarinic and nicotinic Agonists. Low efficacy and poor selectivity of available compounds have limited the clinical utility of Muscarinic Agonists. Recent studies suggesting a role for Muscarinic Agonists in regulating the production of Aβ raise the possibility that selective M1 Agonists could be useful in treating not only the symptoms, but also the underlying cause(s) of Alzheimer’s disease. Thus, renewed efforts have focused on the development of compounds with improved selectivity for M1 receptors and lower toxicity. 5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine (CDD-0102) is a potent M1 agonist with a low side effect profile that enhances memory function in animal models of Alzheimer’s disease. The available preclinical data suggest that CDD-0102 may be useful in the treatment of Alzheimer’s disease.
Steven Mark Bromidge - One of the best experts on this subject based on the ideXlab platform.
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design of r z α methoxyimino 1 azabicyclo 2 2 2 octane 3 acetonitrile sb 202026 a functionally selective azabicyclic Muscarinic m1 agonist incorporating the n methoxy imidoyl nitrile group as a novel ester bioisostere
Journal of Medicinal Chemistry, 1997Co-Authors: Steven Mark Bromidge, Frank Brown, Frederick Cassidy, Michael S G Clark, Steven Dabbs, Michael S Hadley, Julie Hawkins, Loudon Julia Mary, Christopher B Naylor, Barry Sidney OrlekAbstract:Loss of cholinergic function is believed to be implicated in the cognitive decline associated with senile dementia of the Alzheimer type (SDAT). The disease is characterized by progressive loss of Muscarinic receptors located on nerve terminals while postsynaptic Muscarinic M1 receptors appear to remain largely intact. Muscarinic Agonists acting directly on postsynaptic receptors offer the prospect of countering the cholinergic deficit in SDAT. This study describes a novel series of azabicyclic Muscarinic Agonists, which incorporate an oxime ether or modified oxime ether group as an ester bioisostere. Modification of the oxime ether function by the introduction of electron withdrawing groups led to the finding that the (Z)-N-methoxy imidoyl nitrile group serves as a stable methyl ester bioisostere. This culminated in the discovery of the quinuclidinyl N-methoxy imidoyl nitrile R-(+)-(Z)-5g which is a functionally selective Muscarinic M1 partial agonist currently in phase III clinical trials for the treatment of SDAT. The selective profile of R-(+)-(Z)-5g can be rationalized in terms of the relative affinity of the compound at Muscarinic receptor subtypes, the degree of agonist efficacy, and brain penetrancy.
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design of r z alpha methoxyimino 1 azabicyclo 2 2 2 octane 3 acetonitri le sb 202026 a functionally selective azabicyclic Muscarinic m1 agonist incorporating the n methoxy imidoyl nitrile group as a novel ester bioisostere
Journal of Medicinal Chemistry, 1997Co-Authors: Steven Mark Bromidge, Frank Brown, Frederick Cassidy, Michael S G Clark, Steven Dabbs, Michael S Hadley, Julie Hawkins, Loudon Julia Mary, Christopher B Naylor, Barry Sidney OrlekAbstract:Loss of cholinergic function is believed to be implicated in the cognitive decline associated with senile dementia of the Alzheimer type (SDAT). The disease is characterized by progressive loss of Muscarinic receptors located on nerve terminals while postsynaptic Muscarinic M1 receptors appear to remain largely intact. Muscarinic Agonists acting directly on postsynaptic receptors offer the prospect of countering the cholinergic deficit in SDAT. This study describes a novel series of azabicyclic Muscarinic Agonists, which incorporate an oxime ether or modified oxime ether group as an ester bioisostere. Modification of the oxime ether function by the introduction of electron withdrawing groups led to the finding that the (Z)-N-methoxy imidoyl nitrile group serves as a stable methyl ester bioisostere. This culminated in the discovery of the quinuclidinyl N-methoxy imidoyl nitrile R-(+)-(Z)-5g which is a functionally selective Muscarinic M1 partial agonist currently in phase III clinical trials for the treatment of SDAT. The selective profile of R-(+)-(Z)-5g can be rationalized in terms of the relative affinity of the compound at Muscarinic receptor subtypes, the degree of agonist efficacy, and brain penetrancy.
Per Sauerberg - One of the best experts on this subject based on the ideXlab platform.
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Muscarinic Agonists with antipsychotic-like activity : Structure-activity relationships of 1,2,5-thiadiazole analogues with functional dopamine antagonist activity
Journal of medicinal chemistry, 1998Co-Authors: Per Sauerberg, Lone Jeppesen, Preben H. Olesen, Thøger Rasmussen, Michael D. B. Swedberg, Malcolm J. Sheardown, Anders Fink-jensen, Christian Thomsen, Henning Thøgersen, Karin RimvallAbstract:Muscarinic Agonists were tested in two models indicative of clinical antipsychotic activity: conditioned avoidance responding (CAR) in rats and inhibition of apomorphine-induced climbing in mice. The standard Muscarinic Agonists oxotremorine and pilocarpine were both active in these tests but showed little separation between efficacy and cholinergic side effects. Structure-activity relationships of the alkylthio-1,2,5-thiadiazole azacyclic type Muscarinic partial Agonists are shown, revealing the exo-6-(3-propyl/butylthio-1,2, 5-thiadiazol-4-yl)-1-azabicyclo[3.2.1]octane analogues (4a,b and 9a, b) to be the most potent antipsychotic agents with large separation between efficacy and cholinergic side effects. The lack of enantiomeric selectivity suggests the pharmacophoric elements are in the mirror plane of the compounds. A model explaining the potency differences of closely related compounds is offered. The data suggest that Muscarinic Agonists act as functional dopamine antAgonists and that they could become a novel treatment of psychotic patients.
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novel functional m1 selective Muscarinic Agonists synthesis and structure activity relationships of 3 1 2 5 thiadiazolyl 1 2 5 6 tetrahydro 1 methylpyridines
Journal of Medicinal Chemistry, 1992Co-Authors: Per Sauerberg, John S. Ward, Charles H. Mitch, Preben H. Olesen, Malcolm J. Sheardown, Susanne Nielsen, Svend Treppendahl, Tage Honore, Andrew PikeAbstract:A series of novel 3-(3-substituted-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro- 1-methylpyridines (substituted-TZTP; 5a-l, 7a-h, 8, 9c-n, 11, 13j) were synthesized and tested for central Muscarinic cholinergic receptor affinity by using [3H]-oxotremorine-M (Oxo-M) and [3H]-pirenzepine (Pz) as ligands. The potency and efficacy of the compounds for the pharmacological defined M1 and M2 Muscarinic receptors were determined on isolated electrically stimulated rabbit vas deferens and on spontaneously beating isolated guinea pig atria, respectively. Selected compounds were also tested for M3 activity in the isolated guinea pig ileum. The C1-8 alkoxy-TZTP 5a-l analogues all displaced [3H]-Oxo-M and [3H]-Pz with low nanomolar affinity. Depicting chain length against Oxo-M binding and against Pz binding the unbranched C1-8 alkoxy-TZTP (5a-h) derivatives produced U-shaped curves with butoxy- (5d) and (pentyloxy)-TZTP (5e) as the optimum chain length, respectively. This U-shaped curve was also seen in the ability of the compounds 5a-h to inhibit the twitch height in the vas deferens preparation. The (pentyloxy)- (5e) and the (hexyloxy)-TZTP (5f) analogues produced an over 90% inhibition of the twitch height with IC50 values in the low picomolar range. In both the atria and in the ileum preparations 5f had low efficacy and potency. With the (alkylthio)-TZTP (7a-h) analogues the structure-activity relationship was similar to the one observed with the alkoxy (5a-h) analogues, but generally 7a-h had higher receptor affinity and was more potent than the corresponding 5a-h. However, the C3-8 alkyl-TZTP (9c,e,g,h) analogues had 10-100 times lower affinity for the central Muscarinic receptors than the corresponding alkoxy and alkylthio derivatives, and their efficacy in the vas deferens preparation was too low to obtain IC50 values. The unsubstituted TZTP (11) compound was a potent but nonselective Muscarinic agonist. The two 3-(3-butoxy/(hexyloxy)-1,2,5-oxadiazol-4-yl)-1,2,5,6-tetrahy dro-1- methylpyridines (butoxy/hexyloxy)-OZTP; 19a/b) were also synthesized and tested. Both 19a and 19b had much lower affinity for the central Muscarinic receptors than 5d and 5f, and the efficacy of 19a,b was too low to give IC50 values in the vas deferens preparation. Therefore, the C5-6 (alkyloxy)/(alkylthio)-TZTP's represent a unique series of potent functional M1 selective Muscarinic Agonists.
