ABSTRACT
CATALYST and COMFA, two software packages for 3D QSAR studies, were associated to correlate the three-dimensional structures of 75 serotonin 5-HT3 ligands to their biological affinities. The conformational analysis and the influence of chemical function-based alignments (the basis of this association) on final results are discussed in this publication. These two analyses allow for precisely quantitating the weights of significant chemical groups or functions on the biological affinities.
Subject(s)
Quantitative Structure-Activity Relationship , Receptors, Serotonin/drug effects , Serotonin Receptor Agonists/chemistry , Serotonin Receptor Agonists/pharmacology , Computer Simulation , Crystallography, X-Ray , Models, Molecular , Molecular Conformation , Receptors, Serotonin, 5-HT3ABSTRACT
The design and synthesis of a new type of 5-HT3 ligand with subnanomolar affinity are described. The O-dialkylaminoethyloximinothienopyrrolizine structure was deduced from molecular modeling studies by replacement of an amidine moiety by an oximino one.
Subject(s)
Receptors, Serotonin/drug effects , Serotonin Antagonists/chemical synthesis , Serotonin Receptor Agonists/chemical synthesis , Animals , Colon/drug effects , Colon/physiology , Dose-Response Relationship, Drug , Guinea Pigs , In Vitro Techniques , Models, Molecular , Receptors, Serotonin, 5-HT3 , Serotonin Antagonists/pharmacology , Serotonin Receptor Agonists/pharmacology , Structure-Activity RelationshipABSTRACT
A definition of a partial agonists serotonin 5-HT3 pharmacophore was carried out by considering a three-dimensional model which correlates the chemical structures of series of piperazinopyrrolothienopyrazines, piperazinopyridopyrrolopyrazines, piperazinopyrroloquinolaxines, piperazinopyridopyrroloquinoxalines, aminoalkyloximinopyrroloindoles, aminoalkyloximinothienopyrrolizines, and aminoalkyloximinopyrrolizines with the biological affinities. The model is formed by five features corresponding to two hydrogen bond acceptors, one aromatic ring, one hydrophobic group, and one positive ionizable site (quaternary ammonium ions). The nature of the features and the distances between them explain the partial agonist activities of these compounds.
Subject(s)
Receptors, Serotonin/drug effects , Serotonin Receptor Agonists/chemistry , Serotonin Receptor Agonists/pharmacology , Drug Evaluation, Preclinical , In Vitro Techniques , Models, Molecular , Receptors, Serotonin, 5-HT3 , Software , Static Electricity , Structure-Activity RelationshipABSTRACT
The reactivity of catecholamines with nitrogen oxides formed from NO in aerated solutions, nitrite, and peroxynitrite was evaluated. Dopamine and norepinephrine in aerobic buffer (pH 7.4) were almost completely converted to their 6-nitro-derivatives by nitric oxide (NO) at room temperature, while epinephrine was nitrated and above all oxidized. The products obtained from each catecholamine treated with sodium nitrite at pH 4-7 were compared to those produced by NO at pH 7.4. Peroxynitrite, which can nitrate tyrosinyl residues, did not produce nitro-derivatives, only oxidized ones. The physiological relevance, particularly for the vascular and nervous system, is discussed. Catecholamine oxidation reactions could be relevant to physiological conditions and also explain neurotoxicity in Parkinson's disease and aging. Nitration reactions, requiring such high NO concentrations, do not seem possible to occur directly under normal physiological conditions, but could take place in acidic vesicules where nitrite, catecholamines, and their nitrated products could accumulate. Finally, the ability of dopamine to increase 2',5'-cyclic adenosine monophosphate (cAMP) formation in cultured striatal neurons was blocked by its nitration by NO or its nitrogen oxide derivatives.