sabcomeline has been researched along with xanomeline* in 3 studies
3 other study(ies) available for sabcomeline and xanomeline
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Effect of muscarinic receptor agonists xanomeline and sabcomeline on acetylcholine and dopamine efflux in the rat brain; comparison with effects of 4-[3-(4-butylpiperidin-1-yl)-propyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one (AC260584) and N-desmethylclozapine
We have demonstrated that the main metabolite of clozapine, N-desmethylclozapine, has a significant role in the ability of clozapine to improve some aspects of cognition in schizophrenia. Furthermore, there is also evidence to suggest that it is the muscarinic M(1) receptor agonist effect of N-desmethylclozapine that underlies its cognitive effects. In the present study we examined the efficacy of two muscarinic receptor agonists xanomeline and sabcomeline to increase the efflux of acetylcholine and dopamine in rat medial prefrontal cortex and nucleus accumbens. Microdialysis in awake, freely moving rats was used to demonstrate that xanomeline at 10, but not 1 or 3 mg/kg (s.c.), significantly increased acetylcholine efflux in both the medial prefrontal cortex and nucleus accumbens. Sabcomeline, at 1 but not 0.1 or 0.5 mg/kg (s.c.), significantly increased acetylcholine efflux in the medial prefrontal cortex but not the nucleus accumbens. Both xanomeline and sabcomeline dose-dependently increased dopamine efflux in the medial prefrontal cortex but only high dose of xanomeline (10 mg/kg, s.c.) and sabcomeline (1 mg/kg, s.c.) increased that in the nucleus accumbens. The acetylcholine and dopamine efflux induced by xamomeline (10 mg/kg, s.c.) and sabcomeline (1 mg/kg, s.c.) were significantly blocked by the preferential muscarinic M(1) receptor antagonist telenzepine (3 mg/kg, s.c.), but significantly potentiated by the atypical antipsychotic drug risperidone (0.1 mg/kg, s.c.), which does not have much affinity for muscarinic receptor(s). According to the analysis of net-AUC (area under the curve) values of acetylcholine and dopamine levels, the rank order of ability of these drugs to increase acetylcholine or dopamine levels is sabcomeline>xanomeline approximately AC260584>N-desmethylclozapine. The present study suggests that the binding potency of muscarinic M(1) receptors is greatly related to their ability to increase cortical acetylcholine and dopamine efflux, and that this may have some relevance for treatment of the cognitive deficit of schizophrenia. Topics: Acetylcholine; Animals; Antipsychotic Agents; Benzoxazines; Brain; Clozapine; Dopamine; Drug Synergism; Imines; Male; Nucleus Accumbens; Pirenzepine; Prefrontal Cortex; Pyridines; Quinuclidines; Rats; Rats, Sprague-Dawley; Receptor, Muscarinic M1; Receptor, Muscarinic M4; Risperidone; Thiadiazoles | 2008 |
Low-affinity M(2) receptor binding state mediates mouse atrial bradycardia: comparative effects of carbamylcholine and the M(1) receptor agonists sabcomeline and xanomeline.
Carbamylcholine, a nonselective muscarinic receptor agonist, and sabcomeline and xanomeline, functional M(1) receptor-selective agonists with high M(2) receptor affinities, were used to explore the relationship of the M(2) receptor affinity of these agonists to mouse atrial bradycardia and to understand the relationship of the high and low M(2) receptor affinity states to carbamylcholine-induced mouse atrial bradycardia. All three agonists produced bradycardia with sabcomeline (pEC(50) = 6.7) more potent than either carbamylcholine (pEC(50) = 5.9) or xanomeline (pEC(50) = 5.1). Sabcomeline and carbamylcholine produced a rapid, concentration-related bradycardia, which was antagonized by atropine with pK(B) values of 8.6 and 8.9, respectively. In addition, sabcomeline antagonized carbamylcholine-induced bradycardia (pK(B) = 7.48), indicating that sabcomeline was a partial agonist at M(2) receptors. In contrast, xanomeline (up to 10(-5) M), did not antagonize carbamylcholine-induced bradycardia, and atropine (3.0 x 10(-8) M) did not antagonize xanomeline-induced bradycardia, suggesting that xanomeline-induced bradycardia was not mediated by M(2) receptors. Analysis of receptor occupancy curves indicated that bradycardia resulted from the interaction of carbamylcholine with the low- rather than high-affinity state of the M(2) receptor and that sabcomeline was a partial agonist at M(2) receptors in mouse atria. In contrast, similar analysis for xanomeline using the receptor affinity of xanomeline at M(2) receptors (1.8 x 10(-8) M) was not consistent with classical receptor theory. These data document that 1) the low-affinity state of the M(2) receptor is responsible for muscarinic-induced atrial bradycardia, 2) sabcomeline was an M(2) receptor partial agonist, and 3) xanomeline-induced bradycardia was not mediated by activation of M(2) muscarinic receptors. Topics: Animals; Atropine; Bradycardia; Carbachol; Drug Interactions; Heart; Heart Rate; Imines; In Vitro Techniques; Mice; Muscarinic Agonists; Pyridines; Quinuclidines; Receptor, Muscarinic M1; Receptor, Muscarinic M2; Receptors, Muscarinic; Thiadiazoles | 2001 |
Xanomeline compared to other muscarinic agents on stimulation of phosphoinositide hydrolysis in vivo and other cholinomimetic effects.
Activation of muscarinic m1 receptors which are coupled to the phosphoinositide (PI) second messenger transduction system is the initial objective of cholinergic replacement therapy in Alzheimer's disease. Thus, we evaluated the ability of the selective muscarinic receptor agonist (SMRA) xanomeline to stimulate in vivo phosphoinositide (PI) hydrolysis and compared it to a number of direct acting muscarinic agonists, two cholinesterase inhibitors and a putative m1 agonist/muscarinic m2 antagonist. Using a radiometric technique, it was determined that administration of xanomeline robustly stimulated in vivo PI hydrolysis and the effect was blocked by muscarinic antagonists, demonstrating mediation by muscarinic receptors. The non-selective muscarinic agonists pilocarpine, oxotremorine, RS-86, S-aceclidine, but not the less active isomer R-aceclidine, also effectively stimulated PI hydrolysis in mice. Amongst the putative m1 agonists, thiopilocarpine, hexylthio-TZTP as well as xanomeline effectively stimulated PI hydrolysis, but milameline, WAL 2014, SKB 202026 and PD 142505 did not significantly alter PI hydrolysis. Furthermore, WAL 2014 and SKB 202026 inhibited agonist-induced PI stimulation, suggesting that they act as antagonists at PI-coupled receptors in vivo. The cholinesterase inhibitors, tacrine and physostigmine, and the mixed muscarinic m1 agonist/m2 antagonist LU25-109 did not activate in vivo PI hydrolysis. Xanomeline, hexylthio-TZTP and thiopilocarpine were relatively free of cholinergic side effects, whereas milameline, WAL 2014 and SKB 202026 produced non-selective effects. Therefore, these data demonstrate that xanomeline selectively activates in vivo PI hydrolysis, consistent with activation of biochemical processes involved in memory and cognition and xanomeline's beneficial clinical effects on cognition in Alzheimers patients. Topics: Animals; Binding, Competitive; Brain Chemistry; Bridged Bicyclo Compounds, Heterocyclic; Cholinergic Agents; Cholinesterase Inhibitors; Dihydropyridines; Dose-Response Relationship, Drug; Hydrolysis; Hypothermia; Imines; Lithium; Male; Mice; Mice, Inbred Strains; Muscarinic Agonists; Oximes; Parasympathomimetics; Phosphatidylinositols; Physostigmine; Pilocarpine; Pyridines; Quinuclidines; Radioligand Assay; Salivation; Tacrine; Tetrazoles; Thiadiazoles; Tremor | 1998 |