EUROPEAN JOURNAL OF DRUG METABOUSM AND PHARMACOKINETICS, 1994, No 3, pp. 173-178 Design of Histamine Hs-Receptor Agonists and Antagonists WALTER SCHUNACK and HOLGER STARK Freie Universiuit Berlin, Institute of Pharmacy, Berlin, Germany Keywords: Histamine Hj-receptor, agonist, prodrug, antagonist, iodoproxyfan SUMMARY The development of highly potent and selective ligands for the characterization of histamine Hs-receptors is reviewed. In the field of agonists stereoselectively methylated derivatives of the natural ligand are found to have the desired phannacodynamic properties. PhaDnacokinetic properties could be improved by forming bioreversible azomethine prodrogs of the primary amine with benzophenone derivatives. In the antagonist field a number of new leads belonging to different chemical classes are discovered. Potential compounds for drug development are identified. The radiolabelled probe shows high potency and selectivity in functional and binding studies. It is a useful compound for binding assays as well as for the detection and localization of histamine Hs-receptors, INTRODUCTION It is now well established that histamine exerts its various biological actions in brain and in peripheral tissues through stimulation of three receptor subtypes. The existence of the third type of histamine receptor, named Hs-receptor, was first reported by Arrang, Gar- barg, and Schwartz in 1983 [I]. The histamine HHe- ceptor was first characterized as an autoreceptor regu- lating in an inhibitory fashion histamine synthesis in and release from cerebral neurons [2]. The role of histamine as a neurotransmitter was thereby streng- thened. The function of modulating Hs-heteroreceptors on serotoninergic [3], cholinergic [4], noradrenergic [5], dopaminergic [6], and peptidergic [7] neurons was thereafter evidenced in brain and in peripheral tissues. In addition, histamine Hj-receptors were recently de- tected on isolated enterochromaffm-like cells of rat stomach [8] where they may be responsible for a regulation of histamine release and, thereby, gastric acid secretion [9]. Other organs as possible targets for his- tamine Hs-receptor ligands are central nervous system (eNS), lung, and cardiac tissues. The final role of this Please send reprint request to: Prof. Dr. Walter Schumack, Preie Universitiit Berlin. Institute of Pharmacy, KOnigin-Luise- Strasse 2+4, 14195 Berlin. Germany. receptor subtype in different physiological and pharma- cological regulation mechanisms is not fully clear by now. Therefore potent and selective ligands are recom- mended for investigations on receptor functions. DEVELOPMENT OF H3-RECEPTOR AGONISTS The first compounds which were tested at Hs-re- ceptors were selected from the pools of histamine H,- and Hz-receptor ligands [I]. Special development of selective Hs-receptor agonists indicated that only small variations of the endogenous ligand. histamine, is prac- ticable by maintaining or increasing the Hr-receptor activity [10,11]. Structural variations of the aminoethyl side chain by leaving the natural 4-imidazolyl nucleus unchanged led to potent Hs-receptor agonists. The H3- receptor shows high degree of stereoselectivity for his- tamine analogues branched in the side chain [12]. The reference agonist is the (R)-eonfigurated a-monomethy- lated histamine derivative, (R)- a-( -)-methylhistamine. It possesses 1,550% activity at Hr-receptors whereas its (S)-eonfigurated enantiomer shows only 13% activity (histamine = 100%) [2] (Tab. 1). In addition to the high potency, this compound shows also low activity at the other histamine receptor subtypes. This impressive receptor selectivity of (R)-a-(-)- methylhistamine is even