Amines antihistamines

A4 Yes Liver, small intestine, colon Trifluoperazine, tertiary amines, antihistamines, lamotrigine, amitriptyline, cyclobenzaprine, olanzapine... 

Maurer, H. and Pfleger, K., Identification and differentiation of alkyl amine antihistamines and then-metabolites in urine by computerized gas chromatography-mass spectrometry, J. Chromatogr., 430, 31-41, 1988. 

The prototype of the antihistamines based on benzhydrol, diphenhydramine (3), is familiar to many today under the trade name Benadryl . Light-induced bromination of diphenylmethane affords benzhydryl bromide (2). This is then allowed to react with dimethylaminoethanol to give the desired ether. Although no mechanistic studies have been reported, it is not unlikely that I he bromine undergoes SNi solvolysis in the reaction medium the carbonitjm ion then simply picks up the alcohol. It might be noted in passing that the theophyline salt of 4 is familiar to many Iravelers as a motion sickness remedy under the trade name Oram amine . 

In a variation on this approach, p-chlorobenzaldehyde is rst condensed with 2-aminopyridine. Reduction of the resulting iff base (62) affords the corresponding secondary amine. Alkyl-ion with the usual side chain affords the antihistamine, chlor-ramine (64). ... 

Aromatic rings containing more than one hetero atom also yield active antihistamines. Alkylation of 2-aminopyrimidine (6S) with p-methoxybenzyl chloride gives the corresponding secondary amine (66). Alkylation with the usual chloroamine affords thonzylamine (67), Application of the same sequence to 2-aminothiazole (68) affords zolamine (70). ... 

Demethylation of the tricyclic antihistamine 9, with cyanogen bromide gives the secondary amine 10 acylation of that intermediate with ethyl chloroformate affords the nonsedating H-1 antihistaminic agent loratidine (11) [3], It is of interest that this compound does not contain the zwitterionic funcrion which is thought to prevent passage through the blood-brain barrier, characteristic of this class of compounds. 

A slightly more complex Scheme is required for preparation of an antihistaminic agent bearing a secondary amine, e. g., tofenacin (32). In the synthesis of tofenacin, alkylation of the benzhydrol (29) with ethyl bromoacetate affords the alkoxy ester (30) saponification followed by conversion to the methylamide gives (31), which is reduced with lithium aluminum hydride to complete the synthesis of 32. 10... 

A similar sequence starting with the acylation product (76) from metachlorophenylacetonitrile gives the halogenated tricyclic ketone 83. Condensation of that intermediate with ethyl bromoacetate in the presence of zinc (Reformatsky reaction) gives the hydroxyester 84. This product is then in turn dehydrated under acid conditions (85), saponified to the corresponding acid (86), and converted to the dimethyl-amide (87) by way of the acid chloride. The amide function is then reduced to the amine (88) with lithium aluminum hydride catalytic hydrogenation of the exocyclic double bond completes the synthesis of closiramine (89). This compound also exhibits antihistaminic activity. 

Since the order of increasing CL intensity for alkyl amines reacted with Ru(bpy)32+ is tertiary amines > secondary amines > primary amines, pharmaceutical compounds bearing a tertiary amine function (e.g., antihistamine drugs [99], anticholinergic drugs [100], erythromycin [101], and its derivatives [102]) have been sensitively determined after HPLC separation (Table 3). The method was applied to the detection of d- and L-tryptophan (Trp) after separation by a ligand-exchange HPLC [103], The detection limits for d- and L-Trp were both 0.2 pmol per injection. Oxalate in urine and blood plasma samples has also been determined by a reversed-phase ion-pair HPLC (Fig. 18) [104], Direct addition of... 

Rubbing the site of the sting with a crushed dock leaf is a simple yet rapid way of decreasing the extent of the pain. In common with many other weeds, the sap of a dock leaf contains a mixture of natural amines (e.g. urea (III) above), as well as natural antihistamines to help decrease any inflammation. The amines are solvated and, because the sap is water based, are alkaline. Being alkaline, these amines react with methanoic acid to yield a neutral salt, according to... 

Mianserin was the first of the second-generation antidepressants to be developed. It lacked the amine reuptake inhibitory and MAOI actions of the first-generation drugs and also lacked the cardiotoxicity and anticholinergic activity of the TCAs. However, it was sedative (antihistaminic), caused postural hypotension (alpha-1 blockade) and also caused blood dyscrasias and agranulocytosis in a small number of patients. This has limited the use of mianserin in recent years. 

Further illustration for the lack of structural specificity required for antihistaminic activity comes from the finding that ethylenediamines carrying both a benzylamine and an additional aromatic substituent on one of the nitrogens afford a series of useful therapeutic agents. Alkylation of benzylaniline with W-(2-chlorethyl)dimethylamine affords phenbenzamine (54). Treatment of the secondary amine with w-(2-chloroethyl)pyrrolidine affords the antihistamine, histapyrrodine (55). °... 

Amine-based drugs, such as oral antihistamines, are weak bases that are absorbed well by the mucosal cells lining the small intestine, where the pH is alkaline and the drugs tend to lose their protons and become nonionized. 

Histamine Hi receptor antagonists which enter the brain (diphenhydramine, promethazine and others) have sedative actions and polysomnographic recordings have shown that they suppress REM sleep and modestly increase SWS. A rebound in REM sleep sometimes occurs on discontinuation. Stimulation of central Hi and H2 receptors markedly potentiates signals produced by excitatory amino acids and it has been suggested that histamine acts as a waking amine (Schwartz et al., 1986). The effects of centrally acting antihistamines on sleep may be due to inhibition of these effects. 

Sedation is often seen in adults as a side effect of treatment. It is presumably related to a combination of anticholinergic, antihistaminic, and serotonergic effects of this medication. Sedation is seen more often with the tertiary amines than with the secondary amines (Baldessarini, 1996). 

Histamine is an amine found in the cells of all animals (Figure 15.20). The release of histamine in the body is associated with involuntary muscle contraction and dilation of the blood vessels. Allergic reactions release histamine in the body and produce the accompanying side effects associated with hay fever such as coughing, sneezing, and ruimy nose. These effects can be alleviated with the use of antihistamines. 

In pharmacodynamic interactions, the pharmacological effect of a drug is changed by the action of a second drug at a common receptor or bioactive site. For example, low-potency antipsychotics and tertiary amine TCAs have anticholinergic, antihistaminic, a-adrenergic antagonist, and quinidine-Kke effects. Therefore, concurrent administration of chlorpromazine and imipramine results in additive sedation, constipation, postural hypotension, and depression of cardiac conduction. 

Cyproheptadine resembles the phenothiazine antihistaminic agents in chemical structure and has potent H receptor-blocking as well as 5-HT2-blocking actions. The actions of cyproheptadine are predictable from its histamine and 5-HT receptor affinities. It prevents the smooth muscle effects of both amines but has no effect on the gastric secretion stimulated by histamine. It also has significant antimuscarinic effects and causes sedation. 

ANTIHISTAMINE. A synthetic substance essentially structurally analogous to histamine, the presence of which in minute amounts prevents or counteracts the action of excess histamine formed in body tissues. See also Histamine and Histamine Antagonists. Antihistamines are usually complex amines of various types. They find a number of medical uses. 

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