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    • The comparatively low number of H

    2022-05-17

    The comparatively low number of H1R agonists is contrasted by the high number of diverse H1R antagonists. Based on pharmacological classification, they are grouped into different generations by considering their target as well as side effects profile. The first generation “antihistamines” consist of two aromatic elements connected by a mainly three membered bridge to a basic aliphatic tertiary amino functionality. Mepyramine (6), doxylamine (7), and doxepine (11) are few examples based on this general structural construction pattern (Fig. 3). These compounds have in common that they easily penetrate the blood/brain barrier causing sedation (Nicholson et al., 1991) and/or anti-cholinergic effects (Hill, 1990). At higher dosages many examples of these antihistamines also show anesthetic effects therapeutically topically beneficial in urticaria or itch (Murota and Katayama, 2011, Orhan et al., 2007, Panula et al., 2015). Nonetheless, it should also be noted that at high concentrations and due to their cationic–amphiphilic properties, first-generation H1R antagonists can also demonstrate contradictory pro-inflammatory effects that are arbitrated via a direct and receptor-independent activation of Gi-proteins in induced pluripotent stem cells of the immune system (Burde and Seifert, 1996). Interestingly, the class of (polycyclic) neuroleptics has been innovated based on the lead structure of early H1R antagonists. Consequently, it is not unexpected that many of the neuroleptics still hold high H1R antagonist activities causing weight gain and sedative side effects. It has, also, been obvious that the members of family A of rhodopsin-like GPCRs share some structural homology in their sequences and therefore have comparable areas that recognize some structural motifs. These repeatedly publicized fragments are designated as privileged structures. The privileged structures can be noticed in many ligands targeting the biogenic amine receptors in diverse arrangements for receptor preference. In regard to the H1R it is the diaryl component which may be incorporated in a tricyclic ring system, connected by the short chain to the amino moiety. By accomplishing all these structural necessities the highly potent mepyramine (also called pyrilamine (6)) has frequently been used as reference antagonist and for radiolabelling experiments (Panula et al., 2015, Tashiro and Yanai, 2007, Yanai and Tashiro, 2007). Importantly, ligand binding at the H1R has been shown to be stereoselective-dependent. The preference of one stereoisomer can be presented by diverse discriminative ratios for various ligands. These differences may be up to three orders of magnitude (e.g. E-configured (trans) triprolidine vs. Z-configured isomer (cis) (8)), depending on the way of stereo-selective orientation by stereo-center or stereo-axis and, also, on the receptor interaction. Interestingly, with cetirizine (10) the difference between both enantiomers is only two-fold, while “enantiomeric shift” has been exploited to make the more potent (R)-(-) enantiomer levocetirizine (Chen, 2008, Gillard et al., 2002). With the tricyclic ligands, including loratadine (12, Fig. 3), some conformational isomers have been observed. Generally these ligands undergo a swift intraconversion, but in some cases the direction of the piperidine moiety on the bend ring system remains stable and the remaining atropisomers (conformational enantiomers) can be separated (Randall et al., 1979, Remy et al., 1977). It is still uncertain whether these conformational isomers can also be distinguished in vivo, as most experiments in this regard have been conducted on guinea-pig systems and have been verified for human H1Rs regularly for ligands on the market only. Considering the sedative effects of the first generation antihistamines, their clinical utility has been demonstrated to be inadequate, despite the fact that some of the ligands are presently available as (over-the-counter) drugs (OTC) for sleep aids. Concerning the significant pathophysiological role of histamine in allergic conditions, the second generation of antihistamines has been developed. Accordingly, second generation H1R antagonists show markedly lower tendency to induce central side effects due to their polar ionic structures lowering their rate to penetrate through the blood/brain barrier, and enabling them to function as high affinity substrates for ATP-dependent P glycoprotein (PgP) or organic anion transport polypeptide efflux pumps (Broccatelli et al., 2010, Devillier et al., 2008). This approach has been realized by taking advantage of the active metabolites of antihistamines (e.g. hydroxyzine (9) and cetirizine (10), loratadine (12) and desloratadine (13), and terfenadine (14) and fexofenadine (15). Numerous of these compounds have successfully replaced the older first generation H1R antagonists as therapeutic agents for allergic conditions.