Developments in histamine H₁-receptor agonists

Abstract

The story of histamine started in the early 1900’s with the fundamental investigations of Dale et al. [l–3], which recognized the remarkable physiological behavior of this biogenic amine. Scientific progress over the past decades has proved that histamine interacts with specific histamine receptors as a neurotransmitter and nearly all mammalian tissues contain detectable amounts of histamine, while the physiological role is not fully understood. According to their chronological order of discovery, three subtypes of histamine receptors are pharmacologically accepted at present: H₁-, H₂- and H₃-receptors [4–6]. The effects following direct stimulation of these histamine receptors are manifold and depend on species and tissue [7, 8]. The actions of histamine can be mimicked by selective agonists or on the contrary blocked by antagonists. Stimulation of H₁-receptors leads to effects which are predominantly pathophysiological, e.g. contraction of smooth muscles (bronchi, intestine and uterus), dilatation of small blood-vessels (arteriols, veins, capillaries), increase of permeability of capillaries and release of catecholamines from adrenal medulla. Thus the possible role of histamine in allergic and inflammatory disorders has led to the development [9] and clinical introduction [10] of the first “classical H₁-receptor antagonist”. The then synthesized, more potent ethylenediamines (e.g. mepyramine), colamines (e.g. diphenhydramine), propylamines (e.g. pheniramine) and the recently developed “non sedative H₁-receptor blockers”, such as astemizole (Hismanal^R), terfenadine (Teldane^R), loratadine (Lisino^R), ceterizine (Zyrtec^R) or the recently marketed azelastine (Allergodil^R) have up to now been useful drugs for the treatment of allergic disorders (e.g. hay fever, urticaria, drug allergy, asthma, etc.) which are continuously increasing and also for the treatment of insect stings.