piperidines and oxatomide

Histamine H(1) receptor (H1R) expression influences the severity of allergy symptoms. We examined the effect of inverse agonists on H1R gene expression. Two inverse agonists (carebastine and mepyramine), but not the neutral antagonist oxatomide, decreased inositol phosphate accumulation. The inverse agonists also decreased H1R gene expression and down-regulated H1R mRNA below basal expression, while basal H1R mRNA expression was maintained after oxatomide treatment. These results suggest that inverse agonists more potently alleviate allergy symptoms by not only inhibiting stimulus-induced up-regulation of H1R gene expression but also by suppressing basal histamine signaling through their inverse agonistic activity.

Topics: Animals; Butyrophenones; CHO Cells; Cricetinae; Cricetulus; Drug Inverse Agonism; Gene Expression Regulation; HeLa Cells; Histamine Antagonists; Histamine H1 Antagonists; Humans; Inositol Phosphates; Piperazines; Piperidines; Pyrilamine; Receptors, Histamine H1; RNA, Messenger

A series of 4-(diarylhydroxymethyl)-1-[3-(aryloxy)propyl]piperidines was synthesized and evaluated for antiallergy activity. Several analogues had potent activity in the passive foot anaphylaxis (PFA) assay, an IgE-mediated model useful in the detection of compounds possessing antiallergic activity. In particular 1-[4-[3-[4-[bis(4-fluorophenyl)hydroxymethyl]-1-piperidinyl] propoxy]-3-methoxyphenyl]ethanone (1, AHR-5333) was more potent than oxatomide and terfenadine in this assay.

Topics: Anaphylaxis; Animals; Benzhydryl Compounds; Chemical Phenomena; Chemistry; Drug Evaluation, Preclinical; Guinea Pigs; Hypersensitivity; Male; Passive Cutaneous Anaphylaxis; Piperazines; Piperidines; Rats; Rats, Inbred Strains; Structure-Activity Relationship; Terfenadine

We have studied the ability of four H1 antihistamines, ketotifen, oxatomide, clemastine and promethazine, and of disodium cromoglycate (DSCG) to inhibit in vitro histamine release mediated by antigen from passively sensitized human lung and from basophilic leukocytes. Anaphylactic histamine release from human leukocytes is inhibited in a comparable fashion by oxatomide, clemastine and promethazine at concentrations just below those inducing histamine release in the absence of antigen. Ketotifen causes a significantly weaker inhibition without inducing histamine release and DSCG is not at all active in this model. On human lung, oxatomide, clemastine and promethazine give a strong and similar inhibition which is linearly related to the dose. Ketotifen markedly differs in this respect, inhibiting according to a bell-shaped dose-response curve and at concentrations closely comparable to that of DSCG. Thus, we confirm that H1 blockers, such as clemastine and promethazine, inhibit anaphylactic histamine release from basophils and human lung but only at high concentrations which may be cytotoxic. Oxatomide behaves very much like these antihistamines. Ketotifen, on the other hand, gives in both models a different pattern of inhibition, closely mimicking that of DSCG. This suggests that the antianaphylactic activity of ketotifen is not related to its H1 blocker properties and that this effect may be relevant to its therapeutic activity.

Topics: Allergens; Cells, Cultured; Depression, Chemical; Dust; Histamine H1 Antagonists; Histamine Release; Humans; Ketotifen; Leukocytes; Lung; Piperazines; Piperidines; Pollen; Thiophenes