proxyfan and imidazole

Synthesis and biological evaluation of the novel histamine H(3) receptor ligands is described. Two series of ethers (aliphatic and aromatic) have been prepared by four different methods. Compounds were evaluated for their affinities at recombinant human H(3) receptor stably expressed in CHO cells. The ethers show from low to moderate in vitro affinities in nanomolar concentration range. The most potent compound was the 1-[3-(4-tert-butylphenoxy)propyl]-4-piperidino-piperidine 16 (hH(3)R K(i)=100 nM). Several members of the new series investigated under in vivo conditions, proved to be inactive.

Topics: Animals; Binding Sites; CHO Cells; Cricetinae; Cricetulus; Humans; Imidazoles; Ligands; Piperidines; Radioligand Assay; Receptors, Histamine H3; Structure-Activity Relationship

The putative partial H1-receptor agonism of some H3-receptor antagonists belonging to the proxifan series was characterized in a functional in-vitro assay using guinea-pig ileum.. Whole segments of guinea-pig ileum were mounted in Tyrode's solution under isotonic conditions in the presence of atropine (10(-7) M) and were cumulatively treated with histamine as an internal reference. After washout, the putative H1-receptor agonists were added cumulatively to determine agonist potency (pEC50) and intrinsic activity (Emax) relative to histamine. Maximal or supramaximal concentrations of partial agonists, or sufficient concentrations of H1-receptor antagonists were incubated for 3-15 min prior to construction of a second concentration-effect curve to histamine in order to calculate partial agonist or antagonist affinity for the H1 receptor (pKP or pA2 value, respectively).. Several analogues of FUB 372 displayed low H1-receptor affinities (pA2 or pKP 4.2-5.5) except for a methyl benzoate derivative (pA2 = 6.81, Schild plot slope unity). FUB 372, four ortho-substituted derivatives (R = F, CH3, OCH3, CF3), and ciproxifan were weak contractile agents (Emax 9-38%, pEC50 4.73-5.68, histamine: 6.70) susceptible to antagonism by the H1-antihistaminergic drug mepyramine (2.10(-9)-10(-7) M). Agonist potency and H1-receptor affinity of these compounds did not correlate with the data of a set of H1-histaminergic 2-phenylhistamines bearing the same substituents.. A specific subset of proxifans related to FUB 372 and ciproxifan represent a unique type of H1-receptor agonists lacking a basic side chain.

Topics: Animals; Guinea Pigs; Histamine Agonists; Histamine Antagonists; Ileum; Imidazoles; Molecular Structure; Muscle Contraction; Receptors, Histamine H1; Receptors, Histamine H3