Chemistry of Anti-H1 Histamine Antagonists

Casy, A. F.

doi:10.1007/978-3-642-66445-8_4

Cited by 4 publications

(3 citation statements)

References 87 publications

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“…This result seems reasonable when one considers that receptor recognition and differentiation of the two aromatic features of the ligand must be the chief factor responsible for affinity differences between isomers (in many antihistamines, e.g., diphenhydramine, the two aryl groups are identical). 22 The more extreme the difference in aromatic character, e.g., homo vs heteroaryl or homoaryl, the greater is the degree of receptor discrimination between the two aromatic features that is to be expected. An additional factor contributing to the lower antipodal activity ratios of the chiral diphenhydramines as compared with pheniramines may be the greater conformational flexibility of the former class, which results from the ether linkage which extends the distance between the benzylic centre and alkylamino side chain.…”

Section: Discussionmentioning

confidence: 96%

Stereochemical studies of chiral h‐1 antagonists of histamine: The resolution, chiral analysis, and biological evaluation of four antipodal pairs

et al. 1992

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The resolution of the H-1 antihistamines chloropheniramine, dimethindene, carbinoxamine, and mebrophenhydramine is described. The optical purity of antipodal products is investigated by chiral HPLC (use of alpha 1-acid glycoprotein and beta-cyclodextrin columns) and NMR (spectra of beta-cyclodextrin inclusion complexes). Configurational relationships among the group are reviewed and assignments are confirmed and extended by circular dichroism evidence. Affinity constants of antipodal pairs for guinea pig ileum and cerebellum sites, determined by gut bath and binding experiments respectively, are reported together with some in vivo tests in man for central effects. Results are discussed in terms of configurational requirements for activity and variations in antipodal potency ratios within the group.

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Section: Discussionmentioning

confidence: 96%

Stereochemical studies of chiral h‐1 antagonists of histamine: The resolution, chiral analysis, and biological evaluation of four antipodal pairs

et al. 1992

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“…The E: Z potency ratio of 600 after a 15-45 min contact time compares favourably with the reported value of 1 170 (Ison et al 1973) when allowance is made for variations in the experimental conditions, and confirms the high degree of selectivity of the H I receptor for triprolidine over its Z-analogue. This ratio exceeds that exhibited towards related E/Z pairs of aminopropenes by up to two orders of magnitude (Casy 1978). It is of interest that optical antipodes of chlorpheniramine, a reduced analogue of triprolidine, exhibit a similar ratio of activity (608) under the same experimental conditions (Mercer 1989).…”

Section: Compoundmentioning

confidence: 96%

Analogues of Triprolidine: Structural Influences upon Antihistamine Activity

Casy

Ganellin

Mercer

et al. 1992

Journal of Pharmacy and Pharmacology

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The synthesis of some geometrical isomers related to triprolidine is reported. Previous configurational assignments, by UV and proton NMR, are validated by high field nuclear Overhauser enhancement methods and the isomeric purity of tested E- and Z-isomers was greater than 99.5% as assessed by an HPLC method developed for these compounds. Affinity constants for triprolidine (E and Z) in guinea-pig ileum showed a potency ratio of approximately 600 whereas at cerebellar sites this ratio was only approximately 100, suggesting that the H1 receptor in these two tissues may not be identical. In-vivo tests using a lethal dose of compound 48/80 (a potent histamine-releasing agent) demonstrated that triprolidine itself was the most active compound to protect the animal among all the isomeric compounds tested: in all isomeric pairs the E-configuration possessed superior activity over Z. The disposition of the aryl groups in these geometrically constrained compounds mimics that seen in the structurally related chiral pheniramines which are sp3 hybridized and whose absolute stereochemistry is known.

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“…Cyproheptadine, a widely known anti-5-hydroxytryptamine and anti-histamine agent (Casy, 1978), has been shown to depress the electrical excitability of nerves (Riccioppo Neto, 1979) and smooth muscle cells (Lowe, Matthews & Richardson, 1981). Whereas the local anaesthetic effect in nerve seems to be due to a blockade of sodium channels, the action of cyproheptadine in smooth muscle probably involves inhibition of the transmembrane calcium current through slow channels.…”

Section: Introductionmentioning

confidence: 99%

Effects of cyproheptadine on electrophysiological properties of isolated cardiac muscle of dogs and rabbits

Neto

1983

British J Pharmacology

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1The effects of cyproheptadine were studied on cardiac Purkinje and ventricular muscle fibres of the dog and on cells of the sinoatrial (SA) node region of rabbit hearts, by means of electrophysiological techniques. 2 Cyproheptadine (2-8 iM) decreased, in a dose-dependent manner, the plateau amplitude and the action potential duration to 50% repolarization of Purkinje and ventricular muscle cells. Higher concentrations also depressed the action potential amplitude, the overshoot and the maximum rate of rise of the upstroke. These effects were only partially reversed on washing. 2 A four fold increase in Ca concentration of the standard Tyrode solution antagonized the effects of cyproheptadine on the action potential characteristics. 4 The 'slow response' obtained in K-depolarized isoprenaline-treated fibres was blocked by cyproheptadine (4 pM).5 Cyproheptadine (10 jiM) depolarized and suppressed the automaticity of spontaneously beating Purkinje fibres. 6 The frequency of discharge of the SA node cells was slowed or abolished by cyproheptadine (2-4 gM). Atropine (2.6 jIM) did not affect the negative chronotropic effect, whereas adrenaline (5 jM) reversed it. 7 It is suggested that cyproheptadine depresses the slow inward current in all types of myocardial fibres studied. Higher concentrations might also affect the fast inward sodium current system.

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Chemistry of Anti-H1 Histamine Antagonists

Cited by 4 publications

References 87 publications

Stereochemical studies of chiral h‐1 antagonists of histamine: The resolution, chiral analysis, and biological evaluation of four antipodal pairs

Stereochemical studies of chiral h‐1 antagonists of histamine: The resolution, chiral analysis, and biological evaluation of four antipodal pairs

Analogues of Triprolidine: Structural Influences upon Antihistamine Activity

Effects of cyproheptadine on electrophysiological properties of isolated cardiac muscle of dogs and rabbits

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