Histamine chemistry

Agonists - The existence of two receptor populations for histamine raises the interesting question of whether the chemical mechanism of histamine interaction differs between the two receptor types. Some indications of the chemical properties which may differentiate receptor action come from studies of histamine chemistry and from structure-activity considerations of congeners. Histamine in aqueous solution is a mixture of equilibrating species, viz. ionic forms, tautomers and conformers nmr studies confirm earlier pK work indicating a N -H N -H (structures 1 and 2) tautomer ratio of approximately 4 1 for histamine monocation, and a comparable ratio for histamine base. The latter result contrasts with crystal structure data and molecular orbital predictions, and may indicate an influence of solvent on tautomer stability. Recent studies of properties pertinent to consideration of ligand-receptor interactions are conformation (MO calculations and infra-red comparison of solid state and chloroform solutions of histamine base ), electronic charge distribution, metal complexation, and phospholipid inter-... 

The biology of the histamine H3 receptor has been detailed in several recent reviews and will not be discussed in great detail here [1-4]. Rather, we intend to draw attention to the major new biological and medicinal chemistry insights that have emerged in the histamine H3 research community over the last couple of years. 

Although most of the medicinal chemistry effort in the H3 receptor field has been focused on the development of antagonists, there is some interest in agonists as well. Histamine H3 receptor agonists decrease the release of histamine in the central and peripheral nervous system and lead to a weakened histaminergic tone. In the brain, their effects will therefore be comparable to those of Hi receptor antagonists, with sedation and induction of sleep as a prominent observation. Indeed, H3 agonists such as the imidazoles... 

Pihel K, Hsieh S, Jorgenson JW, Wightman RM. Electrochemical detection of histamine and 5-hydroxytryptamine at isolated mast-ceUs. Analytical Chemistry 67,4514-4521, 1995. 

Young R.C., R.C. Mitchell, T.H. Brown, C.R. Ganellin, R. Griffiths, M. Jones, K.K. Rana, D. Saunders, 1. R. Smith, N.E. Sore, and T.J. Wilks (1988). Development of a new physicochemical model for brain penetration and its application to the design of centrally acting H2 receptor histamine antagonists. Journal of Medicinal Chemistry 31 656-671. 

Solid phase attachment of histidine-containing peptides by anchoring the imidazole ring to trityl resins has been developed for combinatorial library preparation of diketopiperazines <99TL809>. Histidine, histamine, and urocanic acid are edl imidazole-containing molecules that have been attached to a trityl-type resin to allow their application to combinatorial chemistry <99TL2825>. 

Disodium cromoglycate (724), marketed as Intal or Cromolyn Sodium, bears some structural resemblance to khellin (457), the spasmolytic component of seeds of Ammi visnaga. Intal is one of the more successful drugs for the prevention of asthmatic attacks, though it is not effective in the treatment of an acute attack of asthma. It appears to prevent the release of histamine and other substances which mediate hypersensitivity reactions but is ineffective once these substances have been released. The chemistry and pharmacology of Intal have been reviewed (B-70MI22402). 

WINDAUS, ADOLF (1876-1959). A German chemist who won the Nobel prize for chemistry in 1928. His work involved the study of steroids and the effect of ultraviolet light activity, ergosterol, and vitamin D2. He also researched digitalis and histamine. Although he studied medicine, he received his doctorate in chemistry at the University of Freiburg. 

Leurs, R., Vollinga, R.C. and Timmerman, H. (1995b). The medicinal chemistry and therapeutic potentials of ligands of the histamine H3-receptor. Prog. Drug Res. 45, 107-165. 

A comprehensive review on imidazole chemistry by Grimmett has appeared recently8. Therefore, the next paragraphs will focus on the most recent developments in the synthesis of substituted imidazoles used as ligands for the histamine receptors. Special attention will be pay to methods with perspective for the synthesis of histaminergic ligands. 

Ganellin, C. R. Characterization and distribution of histamine receptors. In The chemical regulation of biological mechanisms Creighton, A. M. Turner, S. Eds. Royal Society of Chemistry London, U.K., 1982 pp. 1-15. 

Holtje, H.-D. Sippl, W. Molecular modelling studies on histamine H2. and H3-receptor agonists. In Proceedings, XIVth International Symposium on Medicinal Chemistry Awouters, F. Ed. Elsevier Science B.V. Amsterdam, 1997 Vol. 28 pp. 137-148. 

Ganellin, G. R., Durant, G. J. Histamine H2-Receptor Agonists and Antagonists. In M. E. Wolff (Ed.), Burger s Medicinal Chemistry, (4th ed., Chapter 48). New York Wiley Sons, 1981. 

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