- Muscarinic agonists with antipsychotic-like activity: Structure-activity relationships of 1,2,5-thiadiazole analogues with functional dopamine antagonist activity
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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.
- Sauerberg, Per,Jeppesen, Lone,Olesen, Preben H.,Rasmussen, Th?ger,Swedberg, Michael D. B.,Sheardown, Malcolm J.,Fink-Jensen, Anders,Thomsen, Christian,Th?gersen, Henning,Rimvall, Karin,Ward, John S.,Calligaro, David O.,DeLapp, Neil W.,Bymaster, Frank P.,Shannon, Harlan E.
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- The palladium-catalyzed cross-coupling reactions of 3-chloro-4-halogeno-1,2,5-thiadiazoles
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3,4-Dichloro- and 3-chloro-4-halogeno-1,2,5-thiadiazoles (halogeno-: bromo- and iodo-) are involved in Pd-catalyzed cross-coupling reactions under Stille and Suzuki conditions. As a result, by using the commercially available 3,4-dichloro-1,2,5-thiadiazole as substrate, several 3-alkyl-, 3-alkenyl-, 3-alkynyl-and 3-aryl-4-chloro-1,2,5-thiadiazoles can easily be prepared. However, these reactions through direct desymmetrization of the 3,4-dichloro-1,2,5-thiadiazole always occur with side-reactions resulting from the concurrent decomposition of the heterocyclic ring of the starting material. These problems are resolved by involving, in these Pd-catalyzed cross-coupling reactions, the more reactive and selective 3-bromo-4-chloro- and 3-chloro-4-iodo-1,2,5-thiadiazole. These new dihalogeno-1,2,5-thiadiazoles can easily be prepared, via diazotization reaction followed by halogen substitution, from the 3-amino-4-chloro-1,2,5-thiadiazole.
- Merschaert, Alain,Gorissen, Hugo J.
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- Tacrine-xanomeline and tacrine-iperoxo hybrid ligands: Synthesis and biological evaluation at acetylcholinesterase and M1 muscarinic acetylcholine receptors
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We synthesized a set of new hybrid derivatives (7-C8, 7-C10, 7-C12 and 8-C8, 8-C10, 8-C12), in which a polymethylene spacer chain of variable length connected the pharmacophoric moiety of xanomeline, an M1/M4-preferring orthosteric muscarinic agonist, with that of tacrine, a well-known acetylcholinesterase (AChE) inhibitor able to allosterically modulate muscarinic acetylcholine receptors (mAChRs). When tested in vitro in a colorimetric assay for their ability to inhibit AChE, the new compounds showed higher or similar potency compared to that of tacrine. Docking analyses were performed on the most potent inhibitors in the series (8-C8, 8-C10, 8-C12) to rationalize their experimental inhibitory power against AChE. Next, we evaluated the signaling cascade at M1 mAChRs by exploring the interaction of Gαq-PLC-β3 proteins through split luciferase assays and the myo-Inositol 1 phosphate (IP1) accumulation in cells. The results were compared with those obtained on the known derivatives 6-C7 and 6-C10, two quite potent AChE inhibitors in which tacrine is linked to iperoxo, an exceptionally potent muscarinic orthosteric activator. Interestingly, we found that 6-C7 and 6-C10 behaved as partial agonists of the M1 mAChR, at variance with hybrids 7-Cn and 8-Cn containing xanomeline as the orthosteric molecular fragment, which were all unable to activate the receptor subtype response.
- Cirillo, Davide,Dallanoce, Clelia,De Amici, Marco,Holzgrabe, Ulrike,Maspero, Marco,Messerer, Regina,Sotriffer, Christoph,Volpato, Daniela,Yuan Chen, Natalia
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- Hybrid molecules from xanomeline and tacrine: Enhanced tacrine actions on cholinesterases and muscarinic M1 receptors
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A set of amide- and amine-linked hybrid molecules comprising moieties of the orthosteric M1 muscarinic receptor agonist xanomeline and the Cholinesterase inhibitor and allosteric receptor modulator tacrine were prepared with varying spacer length of 10-17 atoms. The hybrids inhibited acetylcholinesterase with similar or higher potency compared to tacrine. M 1 receptor binding affinity was similar or higher relative to xanomeline and far higher relative to tacrine. Affinities hardly changed when the receptors' orthosteric site was occupied by an inverse agonist ligand. When occupied by the orthosteric activator acetylcholine, affinity for the hybrids declined to unmeasureably low levels. Hybrids did not activate M1 receptors. In vivo studies assaying cognition impairment in rats induced by scopolamine revealed pronounced enhancement of scopolamine action. Taken together, instead of dualsteric (simultaneous allosteric/orthosteric) binding, the hybrids seem to prefer purely allosteric binding at the inactive M 1 receptor.
- Fang, Lei,Jumpertz, Sabine,Zhang, Yihua,Appenroth, Dorothea,Fleck, Christian,Mohr, Klaus,Tr?nkle, Christian,Decker, Michael
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scheme or table
p. 2094 - 2103
(2010/08/19)
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- Synthesis and evaluation of xanomeline analogs-Probing the wash-resistant phenomenon at the M1 muscarinic acetylcholine receptor
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A series of xanomeline analogs were synthesized and evaluated for binding at the M1 muscarinic acetylcholine receptor (M1 receptor). Specifically, compounds that substitute the O-hexyl chain of xanomeline with polar, ionizable, or conformationally restricted moieties were assessed for their ability to bind to the M1 receptor in a wash-resistant manner (persistent binding). From our screen, several novel ligands that persistently bind to the M1 receptor with greater affinity than xanomeline were discovered. Results indicate that persistent binding may arise not only from hydrophobic interactions but also from ionic interactions with a secondary M1 receptor binding site. Herein, a qualitative model that accounts for both binding scenarios is proposed and applied to understand the structural basis to wash-resistant binding and long-acting effects of xanomeline-based compounds.
- Kane, Brian E.,Grant, Marianne K.O.,El-Fakahany, Esam E.,Ferguson, David M.
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p. 1376 - 1392
(2008/09/18)
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- PESTICIDAL SUBSTITUTED 1,2,5,-THIADIAZOLE DERIVATIVES
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Insecticidal and acaricidal compositions comprising an insecticidally or acaricidally effective amount of a 1,2,5-thiadiazole of the formula (I); wherein R, Q and m are as defined in admixture with at least one agriculturally acceptable extender or adjuvant are disclosed. In addition, methods of controlling insects and acarids comprising applying said compositions to a locus of crops where control is desired are disclosed.
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Page/Page column 32-33
(2008/06/13)
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- Palladium-catalyzed cross-coupling chemistry on 3-chloro-4-halo-1,2,5-thiadiazole
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The present invention relates to 3-chloro-4-halo-1,2,5-thiadiazole compounds, a method of producing novel mono- and di-substituted-1,2,5-thiadiazoles therefrom, as well as mono- and di-substituted -1,2,5-thiadiazoles.
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- METHOD OF TREATING SCHIZOPHRENIA
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The present invention relates to a novel method for treating a mammal suffering from or susceptible to schizophrenia and schizophreniform diseases by administering thiadiazole or oxadiazole compounds.
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- Heterocyclic compounds
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The present invention relates to therapeutically active azacyclic compounds, a method of preparing the same and to pharmaceutical compositions comprising the compounds. The novel compounds are useful as stimulants of the cognitive function of the forebrai
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- METHOD OF TREATING GASTROINTESTINAL MOTILITY DISORDERS
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The present invention relates to a novel method for treating a mammal suffering from gastrointestinal motility disorders.
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- Method of treating urinary bladder dysfunctions with 3-tetrahydropyridine derivatives
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The present invention relates to a novel method for treating a mammal suffering from urinary bladder dysfunctions.
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- HETEROCYCLIC COMPOUNDS
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The present invention relates to therapeutically active azacyclic compounds, a method of preparing the same and to pharmaceutical compositions comprising the compounds. The novel compounds are useful as stimulants of the cognitive function of the forebrai
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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
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A series of novel 3-(3-substituted-1,2,5-thiadiazol-4-yl)-1,2,5,6- tetrahydro-1-methylpyridines (substituted-TZTP; 5a-1, 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-1 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-tetrahydro-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.
- Sauerberg,Olesen,Nielsen,Treppendahl,Sheardown,Honore,Mitch,Ward,Pike,Bymaster,Sawyer,Shannon
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p. 2274 - 2283
(2007/10/02)
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- Piperidine compounds and their preparation and use
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The present invention relates to therapeutically active piperidine compounds, a method of preparing the same and to pharmaceutical compositions comprising the compounds. The novel compounds are useful as stimulants of the cognitive function of the forebra
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