Novel histamine H(3)-receptor antagonists and partial agonists with a non-aminergic structure.
We determined the affinities of eight novel histamine H(3)-receptor ligands (ethers and carbamates) for H(3)-receptor binding sites and their agonistic/antagonistic effects in two functional H(3)-receptor models. The compounds differ from histamine in that the ethylamine chain is replaced by a propyloxy chain; in the three ethers mentioned below (FUB 335, 373 and 407), R is n-pentyl, 3-methylbutyl and 3,3-dimethylbutyl, respectively. The compounds monophasically inhibited [(3)H]-N(alpha)-methylhistamine binding to mouse cerebral cortex membranes (pK(i) 7.51 - 9.53). The concentration-response curve of histamine for its inhibitory effect on the electrically evoked [(3)H]-noradrenaline overflow from mouse cortex slices was shifted to the right by these compounds (apparent pA(2) 6.61 - 8.00). Only FUB 373 and 407 inhibited the evoked overflow by themselves (intrinsic activities 0.3 and 0.4); these effects were counteracted by the H(3)-receptor antagonist clobenpropit. [(35)S]-GTPgammaS binding to mouse cortex membranes was stimulated by the H(3)-receptor agonist (R)-alpha-methylhistamine in a manner sensitive to clobenpropit. Among the novel compounds only FUB 373 and 407 stimulated [(35)S]-GTPgammaS binding (intrinsic activities 0.6 and 0.4). In conclusion, the novel compounds are partial H(3)-receptor agonists (FUB 373 and 407) or H(3)-receptor antagonists; comparison with FUB 335 shows that the transition from antagonist to agonist is caused by a slight structural change. A protonated N atom in the side chain is not necessary for agonism at H(3) receptors, proposing a receptor-ligand interaction different from that of classical agonists.
Nickel
T
T
Institut für Pharmakologie und Toxikologie, Universität Bonn, Reuterstr. 2b, 53113 Bonn, Germany.
Bauer
U
U
Schlicker
E
E
Kathmann
M
M
Göthert
M
M
Sasse
A
A
Stark
H
H
Schunack
W
W
D000588:Amines / Q000737:chemistry; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004558:Electric Stimulation; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006632:Histamine / Q000494:pharmacology; D017442:Histamine Agonists / Q000737:chemistry / Q000494:pharmacology*; D006633:Histamine Antagonists / Q000494:pharmacology*; D066298:In Vitro Techniques; D008761:Methylhistamines / Q000494:pharmacology; D051379:Mice; D009638:Norepinephrine / Q000378:metabolism; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D018100:Receptors, Histamine H3 / Q000187:drug effects*
D000588:Amines; D017442:Histamine Agonists; D006633:Histamine Antagonists; D008761:Methylhistamines; D018100:Receptors, Histamine H3; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C069357:alpha-methylhistamine; D006632:Histamine; D009638:Norepinephrine