Following the discovery of the human histamine H4 receptor, a high throughput screen of our corporate compound collection identified compound 6 as a potential lead. Investigation of the SAR resulted in the discovery of novel compounds 10e and 10l, which are the first potent and selective histamine H4 receptor antagonists to be described.

Three series of H(4) receptor ligands, derived from indoly-2-yl-(4-methyl-piperazin-1-yl)-methanones, have been synthesized and their structure-activity relationships evaluated for activity at the H(4) receptor in competitive binding and functional assays. In all cases, substitution of small lipophilic groups in the 4 and 5-positions led to increased activity in a [(3)H]histamine radiolabeled ligand competitive binding assay. In vitro metabolism and initial pharmacokinetic studies were performed on selected compounds leading to the identification of indole 8 and benzimidazole 40 as potent H(4) antagonists with the potential for further development. In addition, both 8 and 40 demonstrated efficacy in in vitro mast cell and eosinophil chemotaxis assays.

The characterization and anatomical distribution of 5-hydroxytryptamine (5-HT) 7 receptor binding sites in brain tissue has been hampered by the lack of a specific radioligand. In the present autoradiographic study, we took advantage of 5-HT 1A knockout and 5-HT 1A/1B double-knockout mice to revisit the pharmacological characterization and anatomical localization of 5-HT 7 binding sites in mouse brain using [ The 5-HT 7 receptor is the most recently identified member of the family of G protein-coupled 5-HT receptors (for review, see Vanhoenacker et al., 2000). The 5-HT 7 receptor has been cloned from rat Ruat et al., 1993;Shen et al., 1993), mouse (Plassat et al., 1993), human (Bard et al., 1993), and guinea pig (Tsou et al., 1994). The receptor is positively coupled to adenylate cyclase, preferentially via Gs. It exhibits a high degree of interspecies homology (approximately 95%) but a low sequence homology with other 5-HT receptors (Ͻ40%). In rat and human, three different splice variants have been described to date, which are thought to have similar pharmacology and function (Heidmann et al., 1997;Krobert et al., 2001). The pharmacological profile of the 5-HT 7 receptor is consistent across all tested species and is characterized by high affinity for the 5-HT 1 agonists 5-CT, 5-HT, and 8-OH-DPAT; and the 5-HT 2 antagonists ritanserin, metergoline, mesulergine, and risperidone. Possible physiological functions for this receptor have been suggested, including relaxation in several vascular preparations (Bard et al., 1993;Shen et al., 1993) and circadian rhythm control via the suprachiasmatic nucleus of the hypothalamus Gannon, 2001). Because 8-OH-DPAT has been shown to exhibit a relatively high affinity for the 5-HT 7 receptor, multiple functions formerly ABBREVIATIONS:

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