Antihistamines structures

Figure 7.8 Comparison of old and new antihistamine structures with histamine.

Before heading out on their drive to Aibuquerque, BL and his wife stop at a local pharmacy for some calamine lotion and an antihistamine to keep BL comfortable on the trip. He will be behind the wheel the whole way, because his wife can no longer see well enough to drive. As the pharmacist on duty that day, consider the antihistaminic structures below, and provide this couple with some much-needed pharmaceutical care. 

Woodward s synthesis, 4, 416-419 Chlorophyll b, 4, 382 Chlorophyll c, 4, 382 Chlorophyll d, 4, 382 Chlorophylls, 4, 378 biosynthesis reviews, 1, 99 structure, 4, 370 substituents reactions, 4, 402 Chloroporphyrin e, 4, 404 Chloroprothixene pharmacology, 3, 942 Chloropyramine as antihistamine, 1, 177 Chloropyrifos synthesis, 2, 201 Chloropyrifos-ethyl as insecticide, 2, 516 Chloropyrifos-methyl as insecticide, 2, 516 Chloroquine, 1, 145 adsorption on nucleic acids, 1, 179 as antimalarial, 1, 173, 2, 517 Chloroquine, hydroxy-as antimalarial, 2, 517 Chlorosulfonyl isocyanate cycloaddition reactions... 

X-ray structure, 3, 158-159 Phenazin-l(2H)-one, 3,4-dihydro-synthesis, 2, 69 Phenazopyridine, 1, 145 as urinary tract analgesic, 2, 517 Phenbenzamine as antihistamine, 1, 177 Phencyclidine... 

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 JV-... 

The low order of structural specificity required for classical antihistaminic activity was noted earlier. It has been found possible to substitute an indene nucleus for one of the two aromatic rings that most of these agents possess. The basic side chain may be present as either dimethylaminoethyl or itself cyc-lized to provide an additional fused ring. 

Historically, both the tricyclic antipsychotic and antidepressant agents are derived in almost direct line from a series of tricyclic antihistaminic compounds (see 104 below). Minor changes in structure in some of the newer... 

Therapeutic Function Antihistaminic Chemical Name 10-[2-(1-PyrrolidinyDethyl] phenothiazine Common Name Parathiazine Structural Formula ... 

FIGURE 9.20 Design of multiple ligancl activity, (a) Dual histamine HI receptor and leukotriene receptor antagonist incorporating known antihistaminic properties of cyproheptadine and LTD4. (b) Joint ACE/NEP inhibitor formed from incorporating similarities in substrate structures for both enzymes. From [57],... 

Antihistamines are drags used to counteract the effects of histamine on body organs and structures. Examples of antihistamines include diphenhydramine (Benadryl), loratadine (Claritin), fexofenadine (Allegra), and cetirizine (Zyrtec). A new antihistamine, deslorata-dine (Clarinex), is die active metabolite of loratadine and is intended to eventually replace loratadine (Claritin). Topical corticosteroid nasal sprays such as fluticasone propionate (Flonase) or triamcinolone ace-tonide (Nasacort AQ) are also used for nasal allergy symptoms. See Chapter 56 for more information on die topical corticosteroids. 

The in vivo antihistaminic activity results indicate that all test compounds protected the animals from histamine-induced bronchospasm significantly. Structural activity relationship (SAR) studies indicated that different alkyl substituents on the first position of the triazoloquinazohne ring exerted varied biological activity. 

In this chapter, the voltammetric study of local anesthetics (procaine and related compounds) [14—16], antihistamines (doxylamine and related compounds) [17,22], and uncouplers (2,4-dinitrophenol and related compounds) [18] at nitrobenzene (NB]Uwater (W) and 1,2-dichloroethane (DCE)-water (W) interfaces is discussed. Potential step voltammetry (chronoamperometry) or normal pulse voltammetry (NPV) and potential sweep voltammetry or cyclic voltammetry (CV) have been employed. Theoretical equations of the half-wave potential vs. pH diagram are derived and applied to interpret the midpoint potential or half-wave potential vs. pH plots to evaluate physicochemical properties, including the partition coefficients and dissociation constants of the drugs. Voltammetric study of the kinetics of protonation of base (procaine) in aqueous solution is also discussed. Finally, application to structure-activity relationship and mode of action study will be discussed briefly. 

It was noted, however, that a subset of responses known to be triggered by histamine failed to be blocked by the classical antihistaminic drugs. This, as well as further sophisticated pharmacological work, led to the classification of histamine receptors as and Hg. To simplify grossly, the receptor controls the responses familiar to every hayfever sufferer these effects can be alleviated readily by classicial antihistamines. The latter interestingly bear little or no structural similarity to histamine... 

Nowhere, perhaps, is this phenomenon better illustrated than in the phenothiazine class. The earlier volume devoted a full chapter to the discussion of this important structural class, which was represented by both major tranquilizers and antihistamines. The lone phenothiazine below, flutiazin (130), in fact fails to show the activities characteristic of its class. Instead, the ring system is used as the aromatic nucleus for a nonsteroidal antiinflammatory agent. Preparation of 130 starts with formylation of the rather complex aniline 123. Reaction with alcoholic sodium hydroxide results in net overall transformation to the phenothiazine by the Smiles rearrangement. The sequence begins with formation of the anion on the amide nitrogen addition to the carbon bearing sulfur affords the corresponding transient spiro intermediate 126. Rearomatization... 

Utilizing the same aryl fluoride linker on conventional MeOPEG polymer, these authors also presented a microwave-accelerated liquid-phase synthesis of benzimidazoles (Scheme 7.70) [79]. This bicydic pharmacophore is an important and valuable structural element in medicinal chemistry, showing a broad spectrum of pharmacological activities, such as antihistaminic, antiparasitic, and antiviral effects. 

Ethers are stable toward hydrolysis, yet are hydrolyzed under severe conditions of acidity and temperature. Furthermore, the presence of certain moieties can decrease the high stability of ethers. In the case of aminoalkyl benzhydryl ethers of the general structure (aryl)2CH-0-(CH2)n-NRR, the decrease in stability becomes marked enough to be of pharmaceutical and even pharmacological relevance. This structural motif is a component of various drugs, including some well-known antihistamines and anticholinergics, e.g., diphenhydramine, orphenadrine, and chlorphenoxamine. 

The conventional (or classical) neuroleptics comprise two classes of compounds with distinctive chemical structures 1. the phenothiazines derived from the antihistamine promethazine (prototype chlorpromazine), including Ltillmann, Color Atlas of Pharmacology 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. 

The low structural specificity of the antihistamines has already been noted. It is perhaps not too surprising, therefore, to find Lhat attachment of the basic side chain directly onto one of the. iromatic rings affords active compounds. In an unusual reaction reminiscent of the Claisen rearrangement, benzyl chloride affords the substituted phenol, 46, on heating with phenol itself. Alkyl-.ition of 46 with 2-dimethylaminoethyl chloride gives phenyltolox-.imine (47).Alkylation of that same intermediate (46) with 1-bromo-2-chloropropane, leads to 48. Use of that halide to alkyl-,ite piperidine gives the antihistamine, pirexyl (49). ... 

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