A chemical switch for the modulation of the functional activity of higher homologues of histamine on the human histamine H3 receptor:: Effect of various substitutions at the primary amino function

In ail effort to establish the structural requirements for agonism, neutral antagonism, and inverse agonism at the human histamine H-3 receptor (H3R) we have prepared a series of higher homologues of histamine in which the terminal nitrogen of the side chain has been either mono- or disubstituted with several aliphatic, alicyclic, and aromatic moieties or incorporated in cyclic systems. The novel ligands have been pharmacologically investigated in vitro for their affinities on the human H3R and H4R subtypes by radioligand displacement experiments and for their intrinsic H3R activities via a CRE-mediated P-galactosidase reporter gene assay. Subtle changes of the substitution pattern at the side chain nitrogen alter enormously the pharmacological activity of the ligands, resulting in a series of compounds with a wide spectrum of pharmacological activities. Among the several neutral H3R antagonists identified within this series, compounds 2b and 2h display an H3R affinity in the low nanomolar concentration range (pK(i) values of 8.1 and 8.4, respectively). A very potent and selective H3R agonist (1l, pEC(50) 8.9, alpha = 0.94) and a very potent, though not highly selective, H3R inverse agonist (2k, pIC(50) = 8-9, alpha -0.97) have been identified as well.