Two Novel and Selective Nonimidazole Histamine H3 Receptor Antagonists A-304121 and A-317920: I. In Vitro Pharmacological Effects

• Published in: The Journal of pharmacology and experimental therapeutics 2003-06, Vol.305 (3), p.887-896
• Main Authors: Esbenshade, Timothy A, Krueger, Kathleen M, Miller, Thomas R, Kang, Chae Hee, Denny, Lynne I, Witte, David G, Yao, Betty B, Fox, Gerard B, Faghih, Ramin, Bennani, Youssef L, Williams, Michael, Hancock, Arthur A
• Format: Article
• Language: English
• Subjects: Animals; Binding Sites; Dose-Response Relationship, Drug; Guanosine 5'-O-(3-Thiotriphosphate) - metabolism; Histamine Antagonists - pharmacology; Humans; Male; Neurotransmitter Agents - metabolism; Piperazines - pharmacology; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Histamine H3 - drug effects; Receptors, Histamine H3 - metabolism; Recombinant Proteins - drug effects; Recombinant Proteins - metabolism; Sulfur Radioisotopes
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.102.047183

Histamine H 3 receptor (H 3 R) antagonists enhance neurotransmitter release and are being developed for the treatment of a variety of neurological and cognitive disorders. Many potent histamine H 3 R antagonists contain an imidazole moiety that limits receptor selectivity and the tolerability of this class of compounds. Here we present the in vitro pharmacological data for two novel piperazine amide ligands, A-304121 [4-(3-((2 R )-2-aminopropanoyl-1-piperazinyl)propoxy)phenyl)cyclopropylmethanone] and A-317920 [ N -((1 R )-2-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxo-ethyl-)-2-furamide], and compare them with the imidazole H 3 R antagonists ciproxifan, clobenpropit, and thioperamide. Both A-304121 and A-317920 bind potently to recombinant full-length rat H 3 R(p K i values = 8.6 and 9.2, respectively) but have lower potencies for binding the full-length human H 3 R (p K i values = 6.1 and 7.0, respectively). A-304121 and A-317920 are potent antagonists at rat H 3 R in reversing R -α-methylhistamine [( R )-α-MeHA] inhibition of forskolin-stimulated cAMP formation (p K b values = 8.0 and 9.1) but weak antagonists at human H 3 Rs in cyclase (p K b values = 6.0 and 6.3) and calcium mobilization (p K b values = 6.0 and 7.3) assays in cells co-expressing Gα qi5 -protein. Both compounds potently antagonize native H 3 Rs by blocking histamine inhibition of potassium-evoked [ 3 H]histamine release from rat brain cortical synaptosomes (p K b values = 8.6 and 9.3) and ( R )-α-MeHA reversal of electric field-stimulated guinea pig ileum contractions (p A 2 values = 7.1 and 8.3). A-304121 and A-317920 are also more efficacious inverse agonists in reversing basal guanosine 5′- O -(3-[ 35 S]thio)triphosphate ([ 35 S]GTPγS) binding at the human H 3 R (pEC 50 values = 5.7 and 7.0) than are the imidazole antagonists. These novel and selective piperazine amides represent useful leads for the development of H 3 R antagonist therapeutic agents.