TECHNOLOGIES DRUGDISCOVERY TODAY Scaffold variations in amine warhead of histamine H 3 receptor antagonists Kerstin Wingen 1 , Holger Stark 1,2, * 1 Johann Wolfgang Goethe University, Institute of Pharmaceutical Chemistry, ZAFES/CMP/ICNF, Max-von-Laue-Str. 9, 60438 Frankfurt/Main, Germany 2 Heinrich Heine University, Institute of Pharmaceutical and Medicinal Chemistry, Universitaetsstr. 1, 40225 Duesseldorf, Germany The histamine H 3 receptor (H 3 R) is involved in numer- ous regulatory neurotransmission processes and there- fore, is a prominent target for centrally occurring disease with some promising clinical candidates. Pre- vious research resulted in the identification of a core pharmacophore blueprint for H 3 R antagonists/inverse agonists, which when inserted in a molecule, mostly ensures acceptable affinity. Nevertheless, variations of scaffold and peripheral areas can increase potency and pharmacokinetic profile of drug candidates. The varia- tions in amine scaffolds of antagonists for this aminer- gic GPCR are of special importance. Section editor: David Lloyd – Trinity College, Dublin, Ireland. Introduction The histamine H 3 receptor, one of the known four G-protein coupled histamine receptors (H 1 R–H 4 R), is involved in neuro- nal function and behavior (Stark et al., 2001). Histamine H 3 receptor antagonists/inverse agonists bind to hH 3 autorecep- tors and trigger an enhanced histamine synthesis and libera- tion via a negative feedback mechanism (Berlin et al., 2011). In addition, by binding to H 3 heteroreceptors, they modulate the release of many other neurotransmitters, for example, acet- ylcholine, dopamine, GABA (g-aminobutyric acid), glutamate and substance P (Tiligada et al., 2011). Thus, hH 3 R antagonists/ inverse agonists are able to influence multiple (patho)physio- logical brain functions such as vigilance, memory processes, food intake, and locomotor activity (Stark, 2003). Historically, the first synthesized hH 3 R ligands were hista- mine variations with imidazole scaffolds showing somewhat deficiencies in matters of selectivity and pharmacokinetic properties (Stark et al., 2004). The modification of the sub- stitution pattern and the replacement of the framework of former hH 3 R ligands led to a set of structurally diverse pro- mising non-imidazole hH 3 R antagonists/inverse agonists. Several of these compounds have entered advanced clinical phases for a broad spectrum of mainly central occurring disorders (e.g. narcolepsy, Alzheimer’s disease, schizophre- nia, and epilepsy) (Sander et al., 2008). Pharmacophore of H 3 R antagonists/inverse agonists Since the discovery of the hH 3 R in 1987, many H 3 R ligand series have been synthesized and analyzed (Tiligada et al., 2009). Although H 3 R antagonists/inverse agonists provide a broad structural diversity within their scaffolds, nearly all antagonists demonstrate a similar blueprint structure, con- taining a basic moiety, mostly a tertiary amine, which is substituted by a linking alkyl group, which often possesses another (frequently polar) functionality (Walter et al., 2012). Owing to ionic interactions this basic skeletal moiety is essential for receptor binding (tertiary amine interacts with Asp114 in transmembrane domain III) and as functional warhead is therefore responsible for maintenance of binding properties atH 3 R (Schlegel et al., 2007). The skeletal structure can be attached directly or by a second alkyl spacer by various Drug Discovery Today: Technologies Vol. 10, No. 4 2013 Editors-in-Chief Kelvin Lam – Simplex Pharma Advisors, Inc., Arlington, MA, USA Henk Timmerman – Vrije Universiteit, The Netherlands Scaffold Hopping *Corresponding author: H. Stark (stark@hhu.de) 1740-6749/$ ß 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ddtec.2013.07.001 e483