Pharmacological profile of new thioperamide derivatives at histamine peripheral H1-, H2-, H3-receptors in guinea-pig.
The recent availability of potent and selective ligands, namely R-(alpha)-methylhistamine and thioperamide, led to conclusive progresses as regards histamine H3-receptor knowledge. The aim of this work is to investigate by in vitro tests the pharmacological properties of new amino and methyl derivatives of the H3-antagonist thioperamide. Such original compounds, developed by the modulation of the thioperamide imidazolyl moiety, were assayed at guinea-pig ileal contractile H1-, atrial chronotropic H2- and enteric neuronal H3-receptors. None of the drugs exhibited interaction with H1 or H2 sites. On electrically stimulated ileum, two of the thioperamide methyl derivatives competitively antagonized the inhibitory effect of the H3-agonist R-(alpha)-methylhistamine. On the basis of the Schild analysis, the more active isomer (compound IV) displayed an affinity at H3-receptors only five times lower than thioperamide. These results could contribute to elucidate further the structural features required to develop potent and selective H3-antagonists. On the other hand, to prove the hypothesized apparent heterogeneity between peripheral and central H3-sites, as emerged by pharmacological and binding studies, autoradiographic investigations are in progress.
Barocelli
E
E
Institute of Pharmacology and Pharmacognosy, University of Parma, Italy.
Ballabeni
V
V
Caretta
A
A
Bordi
F
F
Silva
C
C
Morini
G
G
Impicciatore
M
M
D000818:Animals; D004558:Electric Stimulation; D005260:Female; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D006632:Histamine / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008761:Methylhistamines / Q000378:metabolism / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology*; D011969:Receptors, Histamine H1 / Q000187:drug effects* / Q000378:metabolism; D011970:Receptors, Histamine H2 / Q000187:drug effects* / Q000378:metabolism; D018100:Receptors, Histamine H3 / Q000187:drug effects* / Q000378:metabolism
D008761:Methylhistamines; D010880:Piperidines; D011969:Receptors, Histamine H1; D011970:Receptors, Histamine H2; D018100:Receptors, Histamine H3; C025566:4-methylhistamine; D006632:Histamine; C052075:thioperamide