Histamine Analogues, XXXV: 2‐Substituted Histamine Derivatives Containing Classical Moieties of H₂‐Antagonists ‐ a Novel Class of H₁‐Agonists

Abstract

A new type of H1-agonists resulted from the combination of the essential histamine structure with parts of H2-antagonists. 2,4-Disubstituted imidazole derivatives were synthesized by reaction of imidic acid methyl esters with 1,3-dihydroxypropanone, 1,4-dihydroxybutanone or 2-oxo-4-phthalimido-1-butylacetate in liquid NH3. The imidazole intermediates were converted into histamine analogues by simple deprotection, Gabriel synthesis followed by deprotection, or by side-chain elongation via the nitriles and final hydrogenation. The new compounds were screened for H1-activity on the isolated guinea-pig ileum and for H2-antagonistic activity on the isolated guinea-pig right atrium. The substances are comparably weak H1-agonists and moderate H2-blockers.

Nα-Imidazolylalkyl and Pyridylalkyl Derivatives of Histaprodifen: Synthesis and in Vitro Evaluation of Highly Potent Histamine H1-Receptor Agonists

“…Furthermore, the H 1 histaminergic activity of 4 and 5 was slightly enhanced by N α -methylation of these compounds . Efforts to improve activity and selectivity by introduction of bulky groups with a flexible side chain at the 2-position resulted in H 1 -receptor agonists with moderate potency …”

Modelling and mutation studies on the histamine H1-receptor agonist binding site reveal different binding modes for H1-agonists: Asp116 (TM3) has a constitutive role in receptor stimulation

“…Potent and highly selective histamine H~-agonists belong to the class of 2-phenylhistamine analogues [2,3]: compounds llb and lle ( Fig. 1) have H~-agonistic activities of !29% and 112% relative to histamine, respectively [4].…”

“…1), and even six-membered rings such as in 2-pyridylethylamine 4) can replace the imidazole ring of histamine, while retaining Hl-agonist activity [1]. A proximal basic nitrogen (N ~) appears to be crucial for agonistic activity; it is found in all H~-agonists with an activity > 0.1% of that of histamine (compare 4 with $ and 6, Fig.…”

“…Agonist activities measured on the guinea pig ileum of compounds 2-10 relative to histamine (= 100%) were taken from Cooper et al [1]. Relative activities of lla-c were taken from a study by Zingel and Schunack [4]. Compounds 1,3,4,8 and lle have recently been tested on two mutant H:receptors (Thr 2°3 --~ Ala 2°3 and Asn 2°7 --~ Ala 2°7 [5]).…”

“…Relative activities of lla-c were taken from a study by Zingel and Schunack [4]. Compounds 1,3,4,8 and lle have recently been tested on two mutant H:receptors (Thr 2°3 --~ Ala 2°3 and Asn 2°7 --~ Ala 2°7 [5]). Histamine (1), 2-methylhistamine (8) and 2-phenylhistamine (lla) are investigated in the present theoretical study.…”