Structure - activity studies with histamine H3 - receptor ligands

Analogues of thioperamide have been synthesised and tested in vitro on rat cerebral cortex to explore structure-activity relationships with the intention of designing compounds which do not possess the thiourea group of thioperamide and which may have improved brain penetration. Compounds derived from histamine and having an aromatic nitrogencontaining heterocyc1e on the side-chain amino group have been found to act as H3 - antagonists. These have served as leads to provide aryloxyethyl- and aryloxypropylimidazoles which are potent H3 antagonists of histamine. Structure-activity relationships for agonists are brief1y reviewed. Analogues of the very potent and selective agonist, imetit (S-[2-imidazol-4-yl)ethyl]isothiourea) have been studied to explore the transition between agonist, partial agonist and antagonist. The isosteric isourea is also a potent agonist. N,N' -Dibutyl-[S-[3-(imidazol-4-yl)propyl]isothiourea is a very potent antagonist having K¡=1.5 nM.Se han sintetizado análogos de tioperamida. Los compuestos han sido ensayados in vitro para explorar los factores que permitan diseñar compuestos derivados de la tioperamida sin grupo tiourea que mejoren la penetración cerebral. Los compuestos más activos como H3-antagonistas contienen un átomo de nitrógeno aromático hetorocíclico sobre la cadena lateral. Estos compuestos se han empleado como cabeza de serie para obtener potentes H3-antagonistas de histarnina con estructura de ariloxietil y ariloxipropilimidazoles. Las relaciones estructura actividad de agonistas se han revisado brevemente. Se han estudiado un grupo de análogos de (S-[2-imidazol-4-il)etil]isotiourea (imetit) con el objeto de explorar la transición entre agonistas y antagonistas. N,N' -dibutil-[S-[3-(imidazol- 4-il)propil]isotiourea es un muy potente antagonistas que tiene Ki=1.5 nM

Structure - activity studies with histamine H3 - receptor ligands

Se han sintetizado análogos de tioperamida. Los compuestos han sido ensayados in vitro para explorar los factores que permitan diseñar compuestos derivados de la tioperamida sin grupo tiourea que mejoren la penetración cerebral. Los compuestos más activos como H3-antagonistas contienen un átomo de nitrógeno aromático hetorocíclico sobre la cadena lateral. Estos compuestos se han empleado como cabeza de serie para obtener potentes H3-antagonistas de histarnina con estructura de ariloxietil y ariloxipropilimidazoles. Las relaciones estructura actividad de agonistas se han revisado brevemente. Se han estudiado un grupo de análogos de (S-[2-imidazol-4-il)etil]isotiourea (imetit) con el objeto de explorar la transición entre agonistas y antagonistas. N,N' -dibutil-[S-[3-(imidazol- 4-il)propil]isotiourea es un muy potente antagonistas que tiene Ki=1.5 nM.Analogues of thioperamide have been synthesised and tested in vitro on rat cerebral cortex to explore structure-activity relationships with the intention of designing compounds which do not possess the thiourea group of thioperamide and which may have improved brain penetration. Compounds derived from histamine and having an aromatic nitrogen containing heterocyc1e on the side-chain amino group have been found to act as H3 - antagonists. These have served as leads to provide aryloxyethyl- and aryloxypropylimidazoles which are potent H3 antagonists of histamine. Structure-activity relationships for agonists are brief1y reviewed. Analogues of the very potent and selective agonist, imetit (S-[2-imidazol-4-yl)ethyl]isothiourea) have been studied to explore the transition between agonist, partial agonist and antagonist. The isosteric isourea is also a potent agonist. N,N' -Dibutyl-[S-[3-(imidazol-4-yl)propyl]isothiourea is a very potent antagonist having K¡=1.5 nM

Histamine receptor activation by unsaturated (allyl and propargyl) homologs of histamine

The spectrum of agonist activity for three new homologs of histamine (cis- and trans-imidazolylallylamine and imidazolylpropargylamine) was evaluated in the isolated guinea pig ileum and right atrium. The homologs were about three log units less potent than histamine in stimulating contractions of the longitudinal muscles of the ileum, but they were histamine-like, pharmacologically, because they were sensitive to blockade by pyrilamine and resistant to blockade by atropine. In the right atrium, these weak agonists were partially sensitive to blockade by cimetidine. The agonist activity of the cis-isomer in particular was completely blocked by a combination of cimetidine and propranolol, but resistant to reserpine treatment (neuronal catecholamine depletion). Therefore, these homologs of histamine have the ability to stimulate H 1 - and H 2 -histamine receptors and beta -adrenoreceptors in vitro .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44880/1/11_2005_Article_BF01966582.pd

Characterization of histamine H1-receptor binding peptides in guinea pig brain using [125I]iodoazidophenpyramine, an irreversible specific photoaffinity probe.

Aminophenpyramine--i.e., N-(5-[2-(4-aminophenyl)ethanamidopentyl])-N'-(4-methoxybenzyl)-N-m ethyl-N'- (2-pyridinyl)-1,2-ethanediamine, a derivative of mepyramine (pyrilamine), a typical antagonist of histamine at its H1 receptor--was synthesized and converted into [125I)iodoazidophenpyramine, a potential photoaffinity probe for the H1 receptor. In the dark, reversible binding of this probe to cerebellar membranes occurred with a Kd of 1.2 x 10(-11) M and a Bmax of 240 fmol/mg of protein and was inhibited by various H1-receptor antagonists with the expected potencies. These features establish the compound as one of the most potent H1-receptor antagonists known so far. Upon UV irradiation, 5% of the bound radioactivity was covalently incorporated into cerebellar membrane polypeptides as shown by standard NaDodSO4/PAGE. Two bands of 47 and 56 kDa were consistently labeled, labeling being prevented by various H1-receptor antagonists with the expected potencies and stereoselectivity. In the presence of protease inhibitors, labeling of the 56-kDa peptide increased at the expense of the 47-kDa peptide, suggesting that the latter was produced by hydrolysis of the former under the action of membrane proteases. In the absence of 2-mercaptoethanol, a band of 350-400 kDa appeared, apparently at the expense of the lighter bands, suggesting that the latter might be linked by one or more disulfide bridges to a higher molecular mass complex. We propose that at least part of the ligand binding domain of the histamine H1 receptor resides within a subunit of apparent molecular mass 56,000