106243-82-7Relevant academic research and scientific papers
Novel histamine H3 receptor antagonists: Synthesis and evaluation of formamidine and S-methylisothiourea derivatives
Goto, Tomokazu,Sakashita, Hiroshi,Murakami, Kazuki,Sugiura, Masanori,Kondo, Takao,Fukaya, Chikara
, p. 305 - 311 (1997)
In order to obtain a new, potent and selective histamine, H3 receptor antagonist, chemical modifications of thioperamide, a well-known H3 receptor antagonist, were conducted. A new series of compounds has been synthesized by modifying the thiourea and cyclohexyl groups of thioperamide, and tested for H3 receptor affinity by receptor binding assay using plasma membrane from rat cerebral cortex. The thiourea group of thioperamide was found to be replaceable with a basic moiety such as formamidine or S-methylisothiourea. Replacement of the cyclohexyl group in thioperamide by a 1-adamantyl or an exo-2-norbornyl group increased the affinity for H3 receptor. Among the compounds synthesized, N-(1-adamantyl)-N',N'-[3-(4(5)-1H- imidazolyl)pentamethylene]formamidine 3f (AQ0145) showed the highest H3 receptor affinity, having a potent antagonistic activity. This compound was at least 1000-fold more active towards H3 than towards H1 and H2 receptors.
Novel qualitative structure-activity relationships for the antinociceptive actions of H2 antagonists, H3 antagonists and derivatives
Hough,Nalwalk,Li,Leurs,Menge,Timmerman,Carlile,Cioffi,Wentland
, p. 1534 - 1543 (2007/10/03)
Recent studies have shown that cimetidine, burimamide and improgan (also known as SKF92374, a cimetidine congener lacking H2 antagonist activity) induce antinociception after intracerebroventricular administration in rodents. Because these substances closely resemble the structure of histamine (a known mediator of some endogenous analgesic responses), yet no role for known histamine receptors has been found in the analgesia actions of these agents, the structure-activity relationships for the antinociceptive effects of 21 compounds chemically related to H2 and H3 antagonists were investigated in this study. Antinociceptive activity was assessed on the hot- plate and tail-flick tests after intracerebroventricular administration in rats. Eleven compounds induced time-dependent (10-min peak) and dose- dependent antinociceptive activity with no observable behavioral impairment. ED50 values, estimated by nonlinear regression, were highly correlated across nociceptive assays (r2 = 0.98, n = 11). Antinociceptive potencies varied more than 6-fold (80-464 nmol), but were not correlated with activity on H1, H2 or H3 receptors. Although highly potent H3 antagonists such as thioperamide lacked antinociceptive activity, homologs of burimamide and thioperamide containing N-aromatic substituents retained H3 antagonist activity and also showed potent, effective analgesia. A literature review of the pharmacology of these agents did not find a basis for their antinociceptive effects. Taken with previous findings, the present results suggest: 1) these compounds act on the brain to activate powerful analgesic responses that are independent of known histamine receptors, 2) the structure-activity profile of these agents is novel and 3) brain-penetrating derivatives of these compounds could be clinically useful analgesics.
