Histamine agonists

Castillo, J.C. and De Beer, E.J. (1947a). The guinea pig tracheal chain as an assay for histamine agonists. Fed. Proc. 6 315. 

In contrast, H3-selective histamine agonists inhibit acid secretion stimulated by food or pentagastrin in several species. 

Corey EJ, Helal CJ (1996) Catalytic enantioselective synthesis of the second generation histamine agonist cetirizine hydrochloride. Tetrahedron Lett 37 4837-4840... 

On occasions, the useful biological activity may only be a minor property or a side-effect of a compound. The aim then would be to enhance the side-effect and eliminate the major biological activity. The story of the antiulcer agent cimetidine (Fig. 7.29) is a case in point. The desired biological property was selective antagonism of histamine receptors in the stomach. The lead compound was a histamine agonist with a very weak antagonism for the receptors of interest. 

Following release, histamine binds to either HI or H2 histamine receptors causing a variety of effects (listed in Table 9.8). In addition to allergens, several other substances cause histamine release, including radiodiagnostic dyes, some antibiotics, kinins (chemicals released by immune cells) and some venoms. Several synthetic histamine agonists are available for laboratory studies of histamine functions, but there are virtually no clinical indications for histamine receptor agonists. 

A similar study of Cu substitution was carried out by a Wyeth team (113.124.125) who found cyano to be the only group of interest. In their assay (Konzett, histamine agonist, aerosol administration), lla-cyano-ll-deoxy-PGE2 had 1% and the 15(R/S)-methyl derivative (II) 10% the activity of I-PGE2. The cyano group, as well as the methyl group, also were effective llct-sub-stituents in the PGF2p series (see section C). 

Muchowski recently reported -ll-deoxy-lla,12a-difuoro-methylene-PGE2 (HI) to have 5x the potency of I-PGE2 in a guinea pig assay (histamine agonist) when administered by aerosol, and to be equipotent when administered by the intravenous route (126,127). The 13,14-dihydro derivative IV was similarly active, as were the and Eq counterparts. Interestingly, the lla,12a-methylene analogs were essentially inactive. In a clinical trial with mildly asthmatic patients neither III or IV were sufficiently effective to be of interest (126). 

Ozaki, Y, Kume, S., and Ohashi, T, 1984, Effects of histamine agonists and antagonists on luminol-dependent chemiluminescence of granulocytes. Agents Actions 15 182-188. 

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