RESUMO
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.
Assuntos
Antipsicóticos/síntese química , Antagonistas de Dopamina/síntese química , Agonistas Muscarínicos/síntese química , Tiadiazóis/síntese química , Animais , Antipsicóticos/química , Antipsicóticos/farmacologia , Antipsicóticos/toxicidade , Aprendizagem da Esquiva/efeitos dos fármacos , Encéfalo/metabolismo , Antagonistas de Dopamina/química , Antagonistas de Dopamina/farmacologia , Antagonistas de Dopamina/toxicidade , Avaliação Pré-Clínica de Medicamentos , Técnicas In Vitro , Injeções Subcutâneas , Masculino , Camundongos , Modelos Moleculares , Conformação Molecular , Atividade Motora/efeitos dos fármacos , Agonistas Muscarínicos/química , Agonistas Muscarínicos/farmacologia , Agonistas Muscarínicos/toxicidade , Ratos , Ratos Sprague-Dawley , Salivação/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-Atividade , Tiadiazóis/química , Tiadiazóis/farmacologia , Tiadiazóis/toxicidade , Tremor/induzido quimicamenteRESUMO
Complementary DNA (cDNA) encoding human beta-amyloid precursor protein familial Alzheimer's disease (FAD) Swedish mutant (beta APPSM) form was cloned into a mammalian expression vector (PK255) containing the CMV promoter. The vector was transfected into Chinese hamster ovary cells containing human muscarinic m1 receptors (CHO-m1), and clonal cells stably expressing beta APPSM were isolated. The effects of m1-receptor activation by the selective m1 agonist xanomeline and the non-selective muscarinic agonist carbachol on processing of beta APPSM to release soluble APP (APPs) and beta-amyloid peptide (A beta) were compared. Xanomeline stimulated APP release with a potency 1000-fold greater than that observed for carbachol. Concentrations of carbachol and xanomeline producing maximal effects on APPs release reduced the secretion of A beta by 28 and 46%, respectively. These results extend previous studies with xanomeline and suggest that cholinergic replacement therapy for Alzheimer's disease may reduce amyloid deposition.