ABSTRACT
Structure-activity relationships of homopiperazine-containing alkoxybiaryl nitriles employing various D-amino acid moieties and their N-furanoyl analogues were undertaken. This led to A-320436, a potent and selective non-imidazole H(3)-receptor antagonist possessing balanced affinity for both rat and human H(3)-receptors. This compound was shown to demonstrate in vitro and in vivo functional antagonism and is non-neurotoxic at doses (i.p.) up to 163 mg/kg in a general observation test.
Subject(s)
Histamine Antagonists/chemical synthesis , Piperazines/chemical synthesis , Receptors, Histamine H3/drug effects , Animals , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Histamine Antagonists/chemistry , Histamine Antagonists/pharmacology , Humans , Mice , Piperazines/chemistry , Piperazines/pharmacology , Rats , Receptors, Histamine H3/metabolism , Structure-Activity RelationshipABSTRACT
Further SAR studies on novel histamine H(3) receptor antagonists are presented. Compound 14bb is a potent antagonist of both the rat cortical and human clone receptors, and is demonstrated to act functionally as an antagonist in an in vivo mouse dipsogenia model.
Subject(s)
Histamine Antagonists/chemistry , Histamine Antagonists/pharmacology , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Receptors, Histamine H3/chemistry , Receptors, Histamine H3/drug effects , Animals , Humans , Ligands , Mice , Models, Animal , Molecular Structure , Rats , Receptors, Histamine H3/metabolism , Structure-Activity RelationshipABSTRACT
Novel 4'-[(NR1R2-1-yl)]-propoxy-biaryl-4-carboxamides were designed and synthesized. All compounds were tested for affinity at histamine H(3)receptors. Most compounds were highly potent and selective for human and rat H(3) receptors and selected examples such as A-349821 showed functional antagonism of H(3) receptors in vitro and in a mouse dipsogenia model.
Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Amines/chemical synthesis , Amines/pharmacology , Histamine Antagonists/chemical synthesis , Histamine Antagonists/pharmacology , Receptors, Histamine H3/drug effects , Animals , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Chromatography, High Pressure Liquid , Cloning, Molecular , Dogs , Dose-Response Relationship, Drug , Drinking Behavior/drug effects , Haplorhini , Humans , Magnetic Resonance Spectroscopy , Mass Spectrometry , Mice , Radioligand Assay , Rats , Receptors, Biogenic Amine/drug effects , Receptors, Biogenic Amine/metabolism , Structure-Activity RelationshipABSTRACT
Structure-activity relationship studies on novel non-imidazole, D-amino acid containing ligands of histamine 3 receptors are presented. A-304121 is a D-alanine piperazine amide with high affinity at the rat H(3) receptor.
