ABSTRACT
Rational drug design utilizing a receptor homology model of the human muscarinic M1 receptor led to the discovery of the highly potent (Ki = 2 nM), efficacious, and in vivo functionally-selective M1 agonist, WAY-132983.
Subject(s)
Bridged-Ring Compounds/chemistry , Bridged-Ring Compounds/pharmacology , Muscarinic Agonists/chemistry , Muscarinic Agonists/pharmacology , Pyrazines/chemistry , Pyrazines/pharmacology , Receptors, Muscarinic/metabolism , Administration, Oral , Animals , CHO Cells/metabolism , Carbachol/chemistry , Carbachol/metabolism , Carbachol/pharmacology , Cerebral Cortex/metabolism , Cognition Disorders/drug therapy , Computer Simulation , Cricetinae , Crystallography, X-Ray , Drug Design , Drug Evaluation, Preclinical , Humans , Macaca mulatta , Maze Learning/drug effects , Models, Molecular , Phosphatidylinositols/metabolism , Protein Conformation , Pyridines/chemistry , Pyridines/pharmacology , Rats , Receptor, Muscarinic M1 , Receptors, Muscarinic/chemistry , Salivation/drug effects , Structure-Activity Relationship , Thiadiazoles/chemistry , Thiadiazoles/pharmacologyABSTRACT
The authors have reported a case of childhood Thyroid Carcinoma at a Pediatric Service. This report has been justified since this is an uncommon pathology in children and a very unusual clinical picture for children. The etiology and diagnostic have been reviewed by the authors. The clinical investigation as well as the clinical course of the disease has been present. The literature for thyroid cancer in children has also been reviewed. The need for a careful investigation in children with unusual radiologic finding has been emphasized; being the thyroid carcinoma metastasis diagnosis one of the possibilities.
ABSTRACT
A series of alpha-amino-3-(phosphonoalkyl)-2-quinoxalinepropanoic acids was synthesized and evaluated for NMDA receptor affinity using a [3H] CPP binding assay. Functional antagonism of the NMDA receptor complex was evaluated in vitro using a stimulated [3H]TCP binding assay and in vivo by employing an NMDA-induced seizure model. Some analogues also were evaluated in the [3H]-glycine binding assay. Several compounds of the AP-6 type show potent and selective NMDA antagonistic activity both in vitro and in vivo. In particular alpha-amino-7-chloro-3-(phosphonomethyl)-2-quinoxalinepropanoic acid (1) displayed an ED50 of 1.1 mg/kg ip in the NMDA lethality model. Noteworthy is alpha-amino-6,7-dichloro-3-(phosphonomethyl)-2-quinoxalinepropanoic++ + acid (3) with a unique dual activity, displaying in the NMDA receptor binding assay an IC50 of 3.4 nM and in the glycine binding assay an IC50 of 0.61 microM.
