ABSTRACT
Benzyloxyphenethylpiperazines are a new class of high affinity NK1 receptor antagonists. Oral bioavailability and selectivity can be fine tuned by the nature of the substituents on the basic nitrogen atom. Addition of substituents with a carboxylic acid group led to very selective and orally active NK1 antagonists free of interaction with L-type calcium channels.
Subject(s)
Neurokinin-1 Receptor Antagonists , Piperazines/chemical synthesis , Piperazines/pharmacology , Acylation , Alkylation , Animals , Biological Availability , CHO Cells , Carboxylic Acids/chemistry , Carboxylic Acids/pharmacology , Chemical Phenomena , Chemistry, Physical , Cricetinae , Crystallography, X-Ray , Guinea Pigs , Humans , Indicators and Reagents , Models, Molecular , Molecular Conformation , Nitrogen , Pulmonary Edema/chemically induced , Pulmonary Edema/prevention & control , Structure-Activity RelationshipABSTRACT
N-Aminoindoline derivatives were prepared and their 5-lipoxygenase inhibitory activities were evaluated in vitro and compared with those of phenidone and NDGA. Compound 4 presents the most effective 5-LO inhibition.
Subject(s)
Antioxidants/chemical synthesis , Hydroxyurea/analogs & derivatives , Indoles/chemical synthesis , Lipoxygenase Inhibitors , Lipoxygenase Inhibitors/chemical synthesis , Antioxidants/chemistry , Antioxidants/pharmacology , Arachidonate 5-Lipoxygenase/metabolism , Hydroxyurea/chemistry , Hydroxyurea/pharmacology , Indoles/chemistry , Indoles/pharmacology , Lipoxygenase Inhibitors/chemistry , Lipoxygenase Inhibitors/pharmacology , Pyrazoles/pharmacologyABSTRACT
The binding cavity of histamine and histamine antagonists is explored using site directed mutagenesis of the human histamine H1 receptor and the amino acids involved in ligand binding are identified. Whereas Asp107 and Phe199 are important for both agonists and antagonists, two additional amino acids (Asn198 and Trp103) are required for efficient histamine binding. The binding site of antagonists is best defined as resulting from a strong ionic bond to Asp107, an orthogonal interaction between one of the aromatic rings with Phe199, and probably a hydrophobic interaction between the second aromatic ring and the lipophilic amino acids of the upper part of TMIV and TMV. This is consistent with structure-activity data of most described antagonists.
Subject(s)
Histamine H1 Antagonists/pharmacology , Receptors, Histamine H1/genetics , Amino Acid Sequence , Animals , Histamine H1 Antagonists/chemistry , Humans , Molecular Sequence Data , Receptors, Histamine H1/drug effectsABSTRACT
The comparative conformational analysis of four Substance P antagonists (NK1-) having different chemical structures allowed to formulate an hypothesis for a peptidic NK1 pharmacophore. The salient features of this pharmacophore (three aromatic groups and two carbonyl functions) belong to a beta-turn conformation. Thus, this kind of conformation might be the basis for the design of newer pseudo-peptidic and non-peptidic NK1 antagonists.
