Piperazine antihistamines

Hydroxyzine is a piperazine antihistaminic agent that suppresses activity in the subcortical area of the CNS. It has skeletal muscular relaxant properties and exhibits antiemetic, analgesic, and bronchodilating actions. 

The piperazine (cyclizine) antihistamines are listed in Table 4. The piperazine antihistamines, like the hydroxyzines, are closely related to the ethylenediamine antihistamines. It is felt that, since ethylenediamine is on the metabolic pathway of both piperazine and hydroxyzine, it is advisable to avoid the use of piperazine antihistamines in ethylenediamine-sensitive individuals. 

Alkylation of the monobenzhydryl derivative of piperazine ( ) with the same alkylating agent gives oxatomide (59), after removal of the protecting group.This agent shows antihistaminic activity as well as some mediator release inhibiting activity, a... 

Yet another nonsedating zwitterionic H-1 antihistamine consists of the product from metabolism of the terminal hydroxyl of the potent antihistamine hydroxyzine terminating in hydroxymethyl instead of a carboxylic acid. This compound, cetirzine (123), can be obtained in straightforward fashion by alkylation of the monosubstituted piperazine 120 with halide 121, via the amide 122 [27]. 

A somewhat more complex theophylline derivative includes both the purinone nucleus and a piperazine side chain more commonly associated with HI antihistaminic compounds. The starting epoxide, 66, is available from treatment of the anion of purinone 65 with epichlorohydrin. Alkylation of the epoxide with monosubstituted piperazine derivative 67, leads to tazifylline (68) [11]. 

Hf and H Receptors. Histamine exerts its actions by binding to receptors on cell membranes. Two types of histamine receptors, the Hi and H2 receptors, are known specific agonists and antagonists exist for each of these receptors. Black et al. (55) differentiated H and H2 receptors with the compounds, 2-methylhistamine and 4 methylhistamine. 2-Methylhistamine is active on tissues with H receptors 4-methylhistamine is active on tissues with H2 receptors. Classical antihistaminic drugs were developed in the 1930 s these compounds block H but not H2 receptors. Among the clinically used H -blockers are derivatives of ethanolamine, ethylenediamine, alkylamine, piperazine and phenothiazine (32). These agents are valuable in the treatment of... 

Attachment of the basic side chain to the phenothiazine nucleus by means of a carbonyl function apparently abolishes the usual CNS or antihistamine effects shown by most compounds in this class. The product azaclorzine instead is described as an anti anginal agent. Reduction of proline derivative 106 with lithium aluminum hydride gives the corresponding fused piperazine 107. Use of that base to alkylate the chloroamide 109, obtained from acylation of phenothiazine with 3-chloropropionyl chloride, leads to azaclorzine (110). ... 

H -antagonists are well absorbed from the gastrointestinal tract. Following oral administration, antihistaminic effect is manifested within 30 minutes, peak plasma concentration is achieved in 2 to 3 hours and effects usually last 4 to 6 hours. However, drugs in piperazine subgroups especially chlorcyclizine and meclizine, the actions persists for 8 to 12 and 12 to 24 hours respectively. 

The prototype antihistamine of this group is diphenhydramine. It has antimuscarinic and pronounced central sedative properties and also an antitussive effect. The mechanism of the latter is unclear, but diphenhydramine is a common ingredient of propriety preparations for the treatment of coughs and colds. It is an effective anti-emetic, especially useful for prevention and treatment of motion sickness. Because of its anticholinergic properties it is occasionally used in the treatment of mild forms of Parkinson s disease. It is also of use in the treatment of drug-induced extrapyramidal effects. Piperazine derivatives... 

Dihydropyrido[2,3-6][l,5]benzothiazepin-5(6//)-ones (104) were obtained by cyclocondensation of 5 and 2-chloronicotinic acid (103) the reaction of compounds 104 with phosphorus oxychloride and phosphorus pentachloride afforded the corresponding iminochlorides which were refluxed in toluene with piperazines and triethylamine to give compounds 105. These products showed antihistaminic, orexigenic, and antianaphy-... 

The piperazine phenothiazines, as exemplified by fluphenazine, are the most potent members of the phenothiazine group, being at least 50 times more potent than chlorpromazine. Because of the structure of their side chain, members of this series lack anticholinergic, antihistaminic, adrenolytic and sedative effects. However, they are more likely to cause extrapyramidal side effects. 

The early antihistamines. Hi histamine receptor antagonists, bore some structural resemblance to histamine and, like histamine, contained an ethylamine group. However, the structures of the many antihistamines that are available are disparate, and the traditional classification according to chemical structure (ethanolamine, ethy-lenediamine, alkylamine, piperazine, and phenothiazine) is outdated, since the second-generation antihistamines, such as terfenadine and astemizole, do not readily fit into the old classification system (2). 

Teratogenic effects have not been proven in humans, although some piperazine derivatives have teratogenic effects in laboratory animals. Some studies have suggested an association between palate malformation and antihistamines (97-99). 

Cinnarizine and flunarizine are piperazine derivatives with antihistaminic properties and calcium channel blocking activity (SEDA-13, 131) (SEDA-14,136) (SEDA-22, 178). Flunarizine is the difluoro derivative of cinnarizine. Cinnarizine is used to treat motion sickness. 

Cyclizine is a first-generation antihistamine, a piperazine derivative, with sedative and antimuscarinic activity, although its sedative effects are not marked. 

In many of the first-generation, or classical, antihistamines. the terminal nitrogen atom is a simple dinicthylainiiw moiety. The amine may also be part of a heterocyclic stnic-ture. however, as illustrated by (he piperazines, some pin-pylamincs (pyrrolidines and piperidines), some phenMhia-zines. the dibenzocycloheptenes. and (he sccond-generatwn... 

This class of compounds includes the BZDs like diazepam (Valium) and oxazepam (Serax), chlordiaz-epoxide (Librium), meprobamate (carbamate derivative), and related compounds, and buspirone (aryl piperazine derivative), which is an anxioselective drug. A miscellaneous group of drugs includes certain antihistaminic and anticholinergic drugs that are difficult to classify (e.g., hydroxyzine and buclizine). 

Clinically important, potentially hazardous interactions with antihistamines, arsenic, chlorpheniramine, dofetilide, lithium, piperazine, quinolones, sparfloxacin... 

Clinically important, potentially hazardous interactions with alcohol, amiodarone, anticholinergics, antihistamines, barbituates, cisapride, dofetilide, doxazosin, erythromycin, guanethidine, hydralazine, levodopa, lithium, methyldopa, metoclopramide, moxifloxacin, piperazine, quinidine, sibutramine, sotalol, thiazide diuretics, thioridazine... 

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