br Dual acting HR antagonists While the present medicinal ch

Dual-acting HR antagonists While the present medicinal chemistry efforts are mainly focused on selective ligands targeting GPCRs, and particularly on H1R, H3R and H4R selective antagonists/agonists, there were and, also, still are several efforts to develop dual acting H1R/H2R, H1R/H3R and H3R/H4R antagonists (Buschauer, 1988, Kottke et al., 2011, Sadek et al., 2013a, Scannell et al., 2004, Schulze et al., 1994, Taylor-Clark et al., 2005, Wiecek et al., 2011, Wolf et al., 1998). In this regard, a rational approach applying the SARs of the first dual-acting H1R/H2R antagonist, namely icotidine (62), was conducted linking structural parts of classical H1R antagonists with H2R antagonists and led to the discovery of secretin receptor (63) with the most potent dual-acting H1R/H2R antagonist in theses series (Buschauer, 1989, Scannell et al., 2004) (Fig. 7). Interestingly, the approach to develop such compounds was based on the initial work relating the design of dual-acting H1R/H2R agonists for the treatment of arrhythmias (Buschauer, 1989). Despite observed structural optimizations through selection of diverse H1R and H2R pharmacophoric moieties with mutually affinity-enhancing properties, the rationale to develop the class of dual-acting H1R/H2R antagonists for potential pharmacological use in premedication of anesthesia was not convincing to encourage further research interests on this track. Contrary, observations from a preclinical model of nasal congestion demonstrated that H3Rs, in addition to H1Rs, also participate in the histamine-induced nasal congestion and shed light on the necessity to simultaneously block both H1Rs and H3Rs in such conditions (Slack et al., 2011, Taylor-Clark et al., 2005). Based on these preclinical observations and recognizing the need for new treatment options in allergic rhinitis, GSK-1004723 (64) has been developed and proved to be of dual-acting H1R/H3R antagonist properties with long duration of action and a profile suitable for once a day dosing as well as topical application via the intranasal route (Slack et al., 2011). Importantly, the dual-acting H1R/H3R antagonist 64 has completed phase 2 of clinical trials addressing allergic rhinitis with the outcomes indicating its efficacy in human volunteers with allergic rhinitis (www.clinicaltrials.gov). Furthermore, it has been found that some imidazole-based H3R antagonists including thioperamide (35) and clobenpropit (36) do bind to the H4Rs, albeit with affinities different from that of the H3Rs (Gbahou et al., 2006, Hofstra et al., 2003, Jablonowski et al., 2003, Lim et al., 2005). Therefore and in search for further dual-acting H3R/H4R antagonists, several groups focused on the structural development of numerous series of (cyclo)alkyl-substituted imidazole derivatives incorporating different functional moieties (like amides, carbamates, ketones, ureas, esters, and ethers), and explored SARs using different in vitro and in vivo assay systems with the identification of (65) and (66) as dual-acting histamine H3R/H4R antagonists that demonstrate balanced activity in the low nanomolar concentration range at H3R and H4R subtypes (Kottke et al., 2011, Wiecek et al., 2011) (Fig. 7). Also, it is worth-fully to denote that in addition to affinity data some further pharmacological profiling can be designed by efficacy since several ligands have (partial) agonist properties at one HR subtype and (partial) inverse agonist properties at the other target (Kottke et al., 2011). Additional HR ligands with dual or multiple targeting at other than histaminergic receptor subtypes have been described, but that is beyond the scope of this overview.
Conclusion
Conflicts of interest
Acknowledgment Support to BS was provided by a UAEU Program for Advanced Research (UPAR) 2013 Grant (# 31M126), UAE University. Support for this work was kindly provided to HS by the EU COST Actions CM1103 and CM1207 as well by DFG INST 208/664-1 FUGG.