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antihistaminic nctivity. There are exceptions, however an av ideneed by promeihazine. which has greater activity than its nonbranched counterpart. When the curbon adjacent to the Structure-Activity Relationships Hi-anihistamines are now commonly wbdivided into lerminal gen atom is branched, the posäbilily af asym- d groups-the first-generation or classical tamines and the second-generntion or "nonsedating antihis d however, when chiraity exists at this site tamines-based primarily on their general pharmacological Aso, in compounds with an asymmetrically substituted un- metry exists, Stereoselective Hi receptor binding is typicall fles.10.2337 The differences between these two series are saurated carbon chain (pyrabutamine and triprolitinc), however, focus on the structural requirements for the first quirements for Hrantihistaminic action were identified be a salurated carson-oxysen moiety or simply a discussed in more detail in the sections that follow. The geometric isomer typieally disghays higher receptor affinity most detailcd published SAR analyses for antihistamines, than the other The X connecting molety of typieal Hi-antihistamines shown in Figure 23.6. In this stracture. Ar is aryl (includin bon atom. This group, along with the curbon chain, appears to serve primarily as a spacer group for the key pharma- yl, substituted phenyl, and heteroaryl groups such as cophoric moieties. Many antihistamines containing a pyridyl): Ar' is a second aryl or arylmethyl group; X is a itom in the coanecting moiety are chiral and ex stereo- atom of O, C, or N: (CH)), represents a carbon chain, usually ethyl: and NRR' represents a basic, terminal selective receptor binding, For example, in the pheniramine series and curbinoxumine, this atom is chiral, and in vitro amine function, The nature of the connecting aton as well anlyses indicate that enantiomers with the S coniguration to subclassify the first-generation antihistamines a inenerally, the first- second-generation antihista- mines are substantially more lipophilic than the endogenous the diaryl substitution pattern and amine moiety has been have higher Hi receptor affinity 0 dicated in the succeeding sections This diaryl substitution pattem is present in both the first- and second-generation antihistamines and is essen ty difference results primarily from the presence of the two tially a significant Hi receptor affinity.-k Furthermore. aryl rings and the substituted amino moieties and thus may several SAR studies suggest that the two aryl moicties must simply reflect the different structural requirements for an- be able to adopt a noncoplanar conformation relative to tagonist versus agonist action at Hi-receptors each other for optimal interaction with the Hi-receptor.2 The two aromatic systems may be linked. as in the tricyclic nature of the aryl moieties have been used to classify the an- antihistamines (phenothiazines, dihenzocyclobeptanes, and tihistarnines as indicated in the sections that follow heptenes), but again they must be noncoplanar for efive Furhermore, variations in the diaryl groups, receptor interaction. Most Hi-antihistamines contain sub- situeats in one of the aryl rings (usually benzene), and chain or terminal nitrogen among the various dnugs account hese influence histamine potency as well as biodisposition,for differences observed in antihistaminic potency as well discussed for the individual classes of compounds in the pharmacological, biodisposition, and adverse reaction pro- agonist, histamine (or the H-antagonists). This lipophilic The nature of conneeting moiety and the structural X-connecting moieties, and the nature of substitution in the alkyl side files. The ability of these drugs to display an array of phar- In many of the first-generation. cr classical, antihista- macological activities is largely because they can interact mines, the terminal nitrogen atom is a simple cimethyl with Hy rec moiety. The amine may also be part of a he:eroyclic struc- tain the basic pharmacophore required for binding to mus- ture, however, as illustrated by the piperazines, some propyl carinic as weil as adrenergic and serotonergic receptors eptors throughout the body, and that they con- amines (pyrrolidines and piperidines), some phenthiazines. (Table 23.2). The relationships of antihistamine structure he dibenzocycloheptenes. and the second-generation anti these overlapping actions (Hi-anthistaminic, anticholiner histamines. In all cases, the amino moiety is basic, with pK.s gic, and local anesthetic) have been analyzed g from 8.5 to 10, and thus is presumed to be protonated when bound on the receptor. The amine moiety is also im- pcrtant in development of stable, solid dosage forms General Pharmacological and hrough salt formation. Therapeutic Considerations The carbon chain of typical Hi antihistamines consists of two or three atoms 22-24 As a result, the distance betwen the The classieal antihistamines have been used extensively for the symptomatic treatment (sneezing, rhinorrhea, and itching central point of the diaryl ring system and the terminal nitro- gen atom in the extended conformation of these comcounds at yes, nose, an throat) of allergic rhinitis (hay fever, polli- ranges from 5 to 6 angstrams (A). A simlar distance be. nosis), chronic idiopathic urticaria, and several other hista- Iveen these key moieties is observed for those antihista- ine-relatcd diseases. hese uses are clearly attributed to ines with less conformational freedom. In some structural heir ability to counter the action of histamine at peripheral Hirecepiors, which mediate the immune and infiammatory rocesses characteristic of these pathologies. These drugs st relieve the symptoms of allergic diseases the begin- ning of the season when pollen counts are low. The antihista- mines also reduce the number, size, and duration of wheals and itching in chronic urticaria when used promptly. Most clinical evidence suggests that there is no signifieant differ- ence in therapetic efficacy for fiust- and second-generation agents in the treatment of these conditions. The antihista- mines have been widely used to relieve the symptoms of eries, branching of the carbon chain results in reduced