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C Leschke

Publications and source records attributed to C Leschke.

7 recordsLinked to original sources
PubMed2000

Ring-substituted histaprodifen analogues as partial agonists for histamine H(1) receptors: synthesis and structure-activity relationships.

Thirteen racemic benzene ring-substituted analogues of histaprodifen (8a; 2-[2-(3,3-diphenylpropyl)-1H-imidazol-4-yl]ethanamine), a novel lead for potent and selective histamine H(1)-receptor agonists, have been prepared from substituted 4,4-diphenylbutyronitriles 5 via cyclization of the corresponding methyl butyrimidates 6 with 2-oxo-4-phthalimido-1-butyl acetate in liquid ammonia, followed by deprotection. Nitriles 5 were accessible by alkylation of either substituted diphenylmethanes with 3-bromopropionitrile or diethyl malonate with substituted 1-chloro-diphenylmethanes and subsequent standard reactions. The title compounds 8 displayed partial agonism on contractile H(1) receptors of the guinea-pig ileum (E(max) = 2-98% relative to histamine) and, compared with the endogenous agonist, were endowed with agonist potencies of 4-92%. The meta fluorinated (8c) and meta chlorinated (8f) analogues showed the highest relative potency in this series (95% confidence limits 85-99% and 78-102%), but did not exceed the value of the lead 8a (99-124%). Compound 8c (2-[2-[3-(3-fluorophenyl)-3-phenylpropyl]-1H-imidazol-4-yl]ethanamine ) was a partial agonist at contractile H(1) receptors of the guinea-pig aorta (relative potency 154% vs. 100% for histamine) and at relaxation-mediating endothelial H(1) receptors of the rat aorta (relative potency 556% vs. 100% for histamine) and matched with the functional behaviour of 8a. Agonism observed for each compound was sensitive to blockade by the selective H(1)-receptor antagonist mepyramine (pA(2) approximately 9 (guinea-pig) and pA(2) approximately 8 (rat aorta)). All histaprodifen analogues 8 stimulated neither histaminergic H(2)/H(3) nor cholinergic M(3) receptors. They displayed only low to moderate affinity for these sites (H(2): pD'(2) < 5; H(3)/M(3): pA(2) < 6). With regard to the substitution pattern on the benzene ring, there was no correlation between the histaprodifen series and the corresponding derivatives of another selective H(1)-receptor agonist, viz. 2-phenylhistamine.

Animals↗
PubMed1999

Stereoselective inhibition of ethanol-induced gastric lesions in the rat by the H(3)-receptor agonist (R)-alpha-methylhistamine and its (S)-configured isomer.

The histamine H(3) receptor shows high degree of stereoselectivity for histamine analogues branched in the side chain. The hypothesis that gastroprotection by (R)-alpha-methylhistamine could be H(3) receptor-mediated was tested by comparing the effect of (R)-alpha-methylhistamine and of (S)-alpha-methylhistamine on ethanol-induced histologic lesions in the rat gastric mucosa. Extensive damage was caused by 60 min exposure to absolute ethanol, 91% of the mucosa examined being damaged. Conversely only 23% of the mucosa was damaged after pretreatment with (R)-alpha-methylhistamine (100 mg/kg i.g.). In the groups pretreated with (S)-alpha-methylhistamine (55.44 and 166.3 mg/kg i.g.) total damage ranged from 77 to 79%, though it was confined to the upper portion of the mucosa. Morphometric analysis of stained intraepithelial mucosubstances revealed that (R)-alpha-methylhistamine pretreatment resulted in an increase in number and volume of surface mucous cells, not evident after (S)-alpha-methylhistamine pretreatment. Scanning electron microscopy confirmed light microscopy evaluations. The two isomers of alpha-methylhistamine differently affect the response of rat gastric mucosa to absolute ethanol and they appear to differ in their influence on surface mucous cells. A basis for interpreting the effects of the two isomers of alpha-methylhistamine rests on the high degree of stereoselectivity of H(3) receptors and on the different affinities of the two isomers for these receptors.

Animals↗
PubMed1997

Alkyl-substituted amino acid amides and analogous di- and triamines: new non-peptide G protein activators.

Synthesis and pharmacological properties of new potent direct activators of heterotrimeric G proteins are described. Compounds were synthesized from protected amino acids with alkylamines using coupling reagents (CDI, DCC, and EDC). Alkyl-substituted amino acid amides and their corresponding di- and triamines were subjected to structure-activity analysis. All compounds activated membrane-bound HL-60 GTPases in a pertussis toxin-sensitive fashion. This suggests a specific effect of compounds on the carboxy terminus of a defined subclass of heterotrimeric G proteins, i.e., members of the G alpha i subfamily. Elongation of the alkyl chain and increasing the number of amino groups enhanced the potency of compounds on HL-60 membrane-bound GTPase. N-(2,5-Diaminopentyl)dodecylamine (21) was selected to study its mode of action employing purified pertussis toxin-sensitive G proteins. It stimulated G alpha subunits by inducing the release of bound GDP. In contrast to receptors G beta gamma complexes were not required for 21-mediated activation of G alpha. Moderate isoform selectivity of its action was observed within a group of highly homologous members of the Gi subfamily with G alpha o1 being activated at lowest concentrations, whereas higher concentrations were necessary for the stimulation of G alpha i1 or transducin. We conclude that these compounds represent important tools for studying G protein-dependent cellular functions.

Amides↗
PubMed1995

Synthesis and histamine H1 receptor agonist activity of a series of 2-phenylhistamines, 2-heteroarylhistamines, and analogues.

New histamine derivatives characterized by a (substituted) aryl, heteroaryl, benzyl, or heteroarylmethyl substituent in the C2 position of the imidazole ring have been prepared from appropriate imidates or amidines, respectively, and 2-oxo-4-phthalimido-1-butyl acetate (1). The compounds were screened as potential H1 receptor agonists on the isolated guinea pig ileum. The 3-halogenated 2-phenylhistamines (halogen = Br (35) and I (36)) were equipotent with histamine, while 2-(3-(trifluoromethyl)phenyl)histamine (2-[2-(3-(trifluoromethyl)phenyl)-1H-imidazol-4-yl]ethanamine (39)) was significantly more potent than histamine (39: pD2 = 6.81, relative activity = 128%). The 2-substituted histamine analogues were partial H1 receptor agonists on the endothelium-denuded isolated guinea pig aorta with pEC50 values generally smaller than observed on the guinea pig ileum, but the rank order of potency was found to be similar. The contractile effects on guinea pig ileum and aorta, respectively, could be blocked concentration-dependently by the H1 receptor antagonist mepyramine, yielding KB values for mepyramine in the nanomolar range. In vitro compounds 35 and 39 bound to [3H]mepyramine-labeled guinea pig cerebellar membranes with a pKi of 6.1 and 5.9, respectively. However, upon iv administration, 35 (3-100 mg/kg) and 39 (3-300 mg/kg) failed to inhibit the binding of [3H]mepyramine to mouse cerebral cortex in vivo, thereby indicating that these histamine derivatives are not able to penetrate the blood-brain barrier. In functional in vitro studies on histamine H2, H3, and other neurotransmitter receptors the selectivity of 39 was found to be 2138 (H1:H2), > 64 (H1:H3), 1000 (H1:M3), 105 (H1:alpha 1), 708 (H1:beta 1), and 71 (H1:5HT2A). Thus compound 39 is the most potent and selective H1 receptor agonist reported so far. These results make meta-substituted 2-phenylhistamines, especially 2-(3-(trifluoromethyl)phenyl)- and 2-(3-bromophenyl)histamine (39 and 35, respectively) valuable experimental tools for the selective stimulation of histamine H1 receptors and the study of H1 receptor-mediated functions.

Animals↗
PubMed1995

Histamine receptor-dependent and/or -independent activation of guanine nucleotide-binding proteins by histamine and 2-substituted histamine derivatives in human leukemia (HL-60) and human erythroleukemia (HEL) cells.

In dibutyryl cAMP-differentiated human leukemia (HL-60) cells, the potent histamine H1-receptor agonist, 2-(3-chlorophenyl)histamine, activates pertussis toxin (PTX)-sensitive guanine nucleotide-binding proteins (G-proteins) of the Gi-subfamily by a mechanism which is independent of known histamine receptor subtypes (Seifert et al. Mol Pharmacol 45: 578-586, 1994). In order to learn more about this G-protein activation, we studied the effects of histamine and various 2-substituted histamine derivatives in various cell types and on purified G-proteins. In HL-60 cells, histamine and 2-methylhistamine increased cytosolic Ca2+ concentration ([Ca2+]i) in a clemastine-sensitive manner. Phenyl- and thienyl-substituted histamines increased [Ca2+]i as well, but their effects were not inhibited by histamine receptor antagonists. 2-Substituted histamines activated high-affinity GTPase in HL-60 cell membranes in a PTX-sensitive manner, with the lipophilicity of substances increasing their effectiveness. Although HEL cells do not possess histamine receptors mediating rises in [Ca2+]i, 2-(3-bromophenyl)histamine increased [Ca2+]i in a PTX-sensitive manner. It also increased GTP hydrolysis by Gi-proteins in HEL cell membranes. All these stimulatory effects of 2-substituted histamine derivatives were seen at concentrations higher than those required for activation of H1-receptors. In various other cell types and membrane systems, 2-substituted histamine derivatives showed no or only weak stimulatory effects on G-proteins. 2-Substituted histamine derivatives activated GTP hydrolysis by purified bovine brain Gi/Go-proteins and by pure Gi2 (the major PTX-sensitive G-protein in HL-60 and HEL cells). Our data suggest the following: (1) histamine and 2-methylhistamine act as H1-receptor agonists in HL-60 cells; (2) incorporation of bulky and lipophilic groups results in loss of H1-agonistic activity of 2-substituted histamine derivatives in HL-60 cells but causes a receptor-independent G-protein-stimulatory activity; (3) the effects of 2-substituted histamine derivatives on G-proteins are cell-type specific.

Animals↗
PubMed1994

The selective histamine H1-receptor agonist 2-(3-trifluoromethylphenyl)histamine increases waking in the rat.

The effects of the selective histamine H1-receptor agonist, 2-(3-trifluoromethylphenyl)histamine, were studied in rats implanted with electrodes for chronic sleep recordings. 2-(3-Trifluoromethylphenyl)histamine (80-120 micrograms) injected into the left lateral ventricle increased wakefulness, whereas slow wave sleep was reduced. Pretreatment with pyrilamine (2.0 mg/kg) prevented the effects of the H1-receptor agonist on wakefulness and slow wave sleep. Our results further support the involvement of histamine in the modulation of the waking state.

Animals↗