cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine (A-987306), A New Histamine H₄R Antagonist that Blocks Pain Responses against Carrageenan-Induced Hyperalgesia

Abstract

cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine, 4 (A-987306) is a new histamine H(4) antagonist. The compound is potent in H(4) receptor binding assays (rat H(4), K(i) = 3.4 nM, human H(4) K(i) = 5.8 nM) and demonstrated potent functional antagonism in vitro at human, rat, and mouse H(4) receptors in cell-based FLIPR assays. Compound 4 also demonstrated H(4) antagonism in vivo in mice, blocking H(4)-agonist induced scratch responses, and showed anti-inflammatory activity in mice in a peritonitis model. Most interesting was the high potency and efficacy of this compound in blocking pain responses, where it showed an ED(50) of 42 mumol/kg (ip) in a rat post-carrageenan thermal hyperalgesia model of inflammatory pain.

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

“…Additional work has shown that this compound was as efficacious as the nonsteroidal anti-inflammatory drug diclofenac in this model (Hsieh et al, 2010a). Similar effects have also been shown with other H 4 receptor antagonists in this model where once again the maximum effect was similar to diclofenac Cowart et al, 2008;Liu et al, 2008). The amino-pyrimidine H 4 receptor antagonist A-943931 (73) was also effective in the carrageenan model, as well as in a spinal nerve ligation model of neuropathic pain .…”

Molecular modeling and QSAR-based design of histamine receptor ligands

“…(5) UR-PG80 [50] 5.53 § 7.11* < 5 § < 5 § (6) UR-AK478 [50] < 6 § 7.51* < 5 § 8.07* (7) Thioperamide < 5 < 4 7.3 7.2 (8) JNJ7777120 [70] 6.01 5.07 5.65 7.92 (9) Imidazolylcyclopropane [51] 5.07 ‡ < 5 ‡ 8.07 ‡ 6.07 ‡ (10) Dibenzodiazepine [76] 8.11 5.06 5.04 7.55…”

“…As the H 4 R is discussed as a new drug target, numerous studies, with regard to synthesis and pharmacological characterization of H 4 receptor ligands, were carried out [51,70,[71][72][73][74][75].…”

Luciferase Reporter Gene Assay on Human, Murine and Rat Histamine H4 Receptor Orthologs: Correlations and Discrepancies between Distal and Proximal Readouts

“…Reference data are taken from (unless otherwise noted, α values referred to histamine = 1.0):afunctional [ 35 S]GTPγS-binding assay on Sf9 cell membranes co-expressing the hH 4 R, mH 4 R or rH 4 R+G iα2 + β 1γ2 ;b,c,dSteady-state [ 32 P]GTPase assay on Sf9 cell membranes co-expressing: hH 4 R-RGS19+ G iα2 + β 1γ2 b [43], hH 4 R-GAIP+G iα2 + β 1γ2 , rH 4 R or mH 4 R+G iα2 + β 1γ2 + GAIP d [23], hH 4 R+G iα2 + β 1γ2 c (α value of ST-1012 referred to thioperamide = −1.0, [39]);ecalcium mobilization assay in 293-EBNA cells transiently co- expressing the hH 4 R, mH 4 R or rH 4 R with G qi5 [20];f,g,hcalcium mobilization assay in HEK293 cells stably co-expressing the hH 4 R, mH 4 R or rH 4 R with G qi5 f [46], g [44], h [45];i,j,k,lCRE-β-galactosidase reporter gene assay in SK-N-MC cells stably co-expressing: the hH 4 R [40]–[42] or the mH 4 R k [57] with the CRE-β-galactosidase reporter gene;mCRE-luciferase reporter gene assay in HEK293T cells, transiently co-expressing the hH 4 R with the CRE-controlled luciferase reporter gene [27];lSRE-luciferase reporter gene assay in HEK293 cells, co-expressing the human, mouse or rat H 4 R+SRE-luciferase+Gα qi chimeric G-protein [57].…”