Two novel and selective nonimidazole histamine H3 receptor antagonists A-304121 and A-317920: I. In vitro pharmacological effects.
Histamine H3 receptor (H3R) antagonists enhance neurotransmitter release and are being developed for the treatment of a variety of neurological and cognitive disorders. Many potent histamine H3R 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-((2R)-2-aminopropanoyl-1-piperazinyl)propoxy)phenyl)cyclopropylmethanone] and A-317920 [N-((1R)-2-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxo-ethyl-)-2-furamide], and compare them with the imidazole H3R antagonists ciproxifan, clobenpropit, and thioperamide. Both A-304121 and A-317920 bind potently to recombinant full-length rat H3R(pKi values = 8.6 and 9.2, respectively) but have lower potencies for binding the full-length human H3R (pKi values = 6.1 and 7.0, respectively). A-304121 and A-317920 are potent antagonists at rat H3R in reversing R-alpha-methylhistamine [(R)-alpha-MeHA] inhibition of forskolin-stimulated cAMP formation (pKb values = 8.0 and 9.1) but weak antagonists at human H3Rs in cyclase (pKb values = 6.0 and 6.3) and calcium mobilization (pKb values = 6.0 and 7.3) assays in cells co-expressing Galphaqi5-protein. Both compounds potently antagonize native H3Rs by blocking histamine inhibition of potassium-evoked [3H]histamine release from rat brain cortical synaptosomes (pKb values = 8.6 and 9.3) and (R)-alpha-MeHA reversal of electric field-stimulated guinea pig ileum contractions (pA2 values = 7.1 and 8.3). A-304121 and A-317920 are also more efficacious inverse agonists in reversing basal guanosine 5'-O-(3-[35S]thio)triphosphate ([35S]GTP gamma S) binding at the human H3R (pEC50 values = 5.7 and 7.0) than are the imidazole antagonists. These novel and selective piperazine amides represent useful leads for the development of H3R antagonist therapeutic agents.
Esbenshade
Timothy A
TA
Neuroscience Research, Global Pharmaceutical Research Division, Abbott Laboratories, R4MN, AP9A, 100 Abbott Park Road, Abbott Park, IL 60064, USA. Tim.Esbenshade@Abbott.com
Krueger
Kathleen M
KM
Miller
Thomas R
TR
Kang
Chae Hee
CH
Denny
Lynne I
LI
Witte
David G
DG
Yao
Betty B
BB
Fox
Gerard B
GB
Faghih
Ramin
R
Bennani
Youssef L
YL
Williams
Michael
M
Hancock
Arthur A
AA
D000818:Animals; D001665:Binding Sites; D004305:Dose-Response Relationship, Drug; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006633:Histamine Antagonists / Q000494:pharmacology*; D006801:Humans; D008297:Male; D018377:Neurotransmitter Agents / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000187:drug effects / Q000378:metabolism*; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D013462:Sulfur Radioisotopes
C475225:4-((3-(4-(2-aminopropanoyl)-1-piperazinyl)propoxy)phenyl)cyclopropylmethanone; D006633:Histamine Antagonists; C475226:N-(2-(4-(3-(4-(cyclopropylcarbonyl)phenoxy)propyl)-1-piperazinyl)-1-methyl-2-oxoethyl)-2-furamide; D018377:Neurotransmitter Agents; D010879:Piperazines; D018100:Receptors, Histamine H3; D011994:Recombinant Proteins; D013462:Sulfur Radioisotopes; D016244:Guanosine 5'-O-(3-Thiotriphosphate)