- Nα-Imidazolylalkyl and Pyridylalkyl Derivatives of Histaprodifen: Synthesis and in Vitro Evaluation of Highly Potent Histamine H1-Receptor Agonists
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A novel series of Nα-imidazolylalkyl and pyridylalkyl derivatives of histaprodifen (6, 2-[2-(3,3-diphenylpropyl)imidazol-4-yl]ethanamine) was synthesized and evaluated as histamine H1-receptor agonists. The title compounds displayed partial agonism at contractile H1-receptors of guinea pig ileum and were at least equipotent with histamine. Agonist effects of the new derivatives were susceptible to blockade by the H1-receptor antagonist mepyramine (2-100 nM). In the imidazole series, suprahistaprodifen (51, [2-[2-(3,3-diphenylpropyl)-1H-imidazol-4-yl]ethyl]-[2-(1H-imidazol-4-yl) ethyl]amine, Nα-2-[(1H-imidazol-4-yl)ethyl]histaprodifen) showed the highest H1-receptor agonist potency ever reported in the literature (pEC50 8.26, efficacy Emax 96%). Elongation of the alkyl spacer from ethyl to butyl decreased activity from 3630% (ethyl, 51) to 163% (butyl, 53) of histamine potency. The exchange of the terminal imidazole nucleus for a pyridine ring resulted in compounds with comparably high potency. A decrease in agonist potency and efficacy was observed when the attachment of the alkyl spacer was consecutively changed from the ortho to the meta and the para position, respectively, of the pyridine ring. The pyridine series that contained a butyl chain possessed the highest potency and affinity. Nα-[4-(2-pyridyl)butyl]histaprodifen (56) emerged as a strong partial agonist, being almost equipotent with 51 (pEC50 8.16, E max 89%). Compounds 51 and 56 also showed potent partial agonism at contractile H1 receptors in guinea pig aorta and potently activated H1-receptor-mediated endothelium-dependent relaxation in the rat aorta. Compounds 51-65 displayed low to moderate affinity at H2, H3, and M3 receptors in functional models of guinea pig. Collectively, Nα-imidazolylalkyl- and Nα -pyridylalkyl-substituted histaprodifens represent a novel class of potent H1-receptor agonists. These compounds may be useful to define the (patho)physiological role of the H1-receptor and refine molecular models of H1-receptor activation.
- Menghin, Sonja,Pertz, Heinz H.,Kramer, Kai,Seifert, Roland,Schunack, Walter,Elz, Sigurd
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- POLY(PHOSPHOESTERS) FOR DELIVERY OF NUCLEIC ACIDS
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Disclosed are polymers comprising the moiety A, which is a moiety of formula I: and pharmaceutically acceptable salts thereof, wherein R, R1, R2, L, n1 and n2 are as defined herein. These polymers are useful for delivering nucleic acids to subject. These polymers and pharmaceutically acceptable compositions comprising such polymers and nucleic acids can be useful for treating various diseases, disorders and conditions.
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Paragraph 0401; 0402
(2020/09/15)
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- Chiral imidazoyl intermediates for the synthesis of 2-(4-imidazoyl)-cyclopropyl derivatives
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Novel intermediates useful in the preparation of optically active H3 histamine receptor antagonist 2-(4-imidazoyl)-cyclopropyl derivatives are disclosed.
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- Steric enhancement of imidazole basicity in cis-urocanic acid derivatives: Models for the action of chymotrypsin
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To test the hypothesis that substrate-induced steric compression between His 57 and Asp 102 at the active site of chymotrypsin can increase the basicity of His 57, we have synthesized the cis- and trans-isomers of 2- bromo-3-(N-tritylimidazole)-2-propenoic acid and 2-chloro-3(N- tritylimidazole)-2-propenoic acid and compared selected properties with those of cis- and trans-urocanic acids. The cis-isomers display low field 1H NMR signals at 17 ppm in dimethylsulfoxide, similar to cis-urocanic acid; whereas the trans-isomers do not show strong hydrogen bonds. Increasing the size of the C2 substituent (H Cl Br) in the cis-isomers increases the pK(a) of the imidazolium group from 6.78 for H to 7.81 and 9.10 for Cl and Br, respectively; whereas the pK(a)s of the trans isomers are all 6.0 ± 0.1. The results indicate that the cis-urocanic acid derivatives with large substituents at C2 act as proton sponges in water, and they support the concept that steric compression in the catalytic triad of chymotrypsin can increase the basicity of His 57.
- Cloninger, Mary J.,Frey, Perry A.
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p. 323 - 333
(2007/10/03)
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