Summary
We determined the affinities of nordimaprit, homodimaprit, clobenpropit and imetit for H3 binding sites (labelled by 3H-Nα-methylhistamine) in rat brain cortex homogenates and their potencies at presynaptic H3A receptors on noradrenergic nerve endings in mouse brain cortex slices.
3H-Nα-Methylhistamine bound saturably to rat brain cortex homogenates with a Kd of 0.70 nmol/l and a Bmax of 98 fmol/mg protein. Binding of 3H-Nα-methylhistamine was displaced monophasically by dimaprit (pKi 6.55), nordimaprit (5.94), homodimaprit (6.44), clobenpropit (9.16), imetit (9.83), R-(−)-α-methylhistamine (8.87) and histamine (8.20), and biphasically by burimamide (pKi high 7.73, pKi low 5.97). In superfused mouse brain cortex slices preincubated with 3H-noradrenaline, the electrically (0.3 Hz) evoked tritium overflow was inhibited by imetit (pIC35 8.93),R-(−)-α-methylhistamine (7.87) and histamine (7.03). The effect of histamine was attenuated by nordimaprit, homodimaprit, clobenpropit and N-ethoxycarbonyl-2- ethoxy-1,2-dihydroquinoline (EEDQ); EEDQ (but not nordimaprit, homodimaprit and clobenpropit) attenuated the effect of histamine also in slices pre-exposed to the drug 60–30 min prior to superfusion. The concentration-response curve of histamine was shifted to the right by homodimaprit and clobenpropit; Schild plots yielded straight lines with a slope of unity for both drugs (pA2 5.94 and 9.55, respectively). Nordimaprit depressed the maximum effect of histamine (pD′2 5.55) and also slightly increased the concentration of histamine producing the half-maximum effect.
In conclusion, nordimaprit and homodimaprit possess similar affinities for H3 binding sites like dimaprit; nordimaprit and homodimaprit as well as clobenpropit and imetit do not differentiate between H3A and H3B binding sites. Nordimaprit is a reversible noncompetitive H3 receptor antagonist, homodimaprit and clobenpropit are reversible competitive H3 receptor antagonists and imetit is an H3 receptor agonist.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Arrang JM, Garbarg M, Lancelot JC, Lecomte JM, Pollard H, Robba M, Schunack W, Schwartz JC (1987) Highly potent and selective ligands for histamine H3-receptors. Nature 327:117–123
Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254
Clark MA, Korte A, Myers J, Egan RW (1992) High affinity histamine H3 receptors regulate ACTH release by AtT-20 cells. Eur J Pharmacol 210:31–35
Furchgott RF (1972) The classification of adrenoceptors (adrenergic receptors). An evaluation from the standpoint of receptor theory. In: Blaschko H, Muscholl E (eds) Handbook of experimental pharmacology, vol XXXIII. Springer, Berlin Heidelberg New York, pp 283–335
Garbarg M, Arrang J-M, Rouleau A, Ligneau X, Dam Trung Tuong M, Schwartz J-C, Ganellin CR (1992) S-[2-(4-Imidazolyl)ethyl]-isothiourea, a highly specific and potent histamine H3 receptor agonist. J Pharmacol Exp Ther 263:304–310
Hey JA, del Prado M, Egan RW, Kreutner W, Chapman RW (1992) Inhibition of sympathetic hypertensive responses in the guinea-pig by prejunctional histamine-H3 receptors. Brit J Pharmacol 107: 347–351
Howson W, Parsons ME, Raval P, Swayne GTG (1992) Two novel, potent and selective histamine H3 receptor agonists. Bioorg Medicinal Chem Lett 2:77–78
Jansen FP, Rademaker B, Bast A, Timmerman H (1992) The first radiolabeled histamine H3 receptor antagonist, [125I]iodophenpropit: saturable and reversible binding to rat cortex membranes. Eur J Pharmacol 217:203–205
Kathmann M, Schlicker E (1992) Dimaprit, nordimaprit and homodimaprit: affinities for H3 binding sites and antagonistic potencies in a functional H3 receptor model. Naunyn-Schmiedeberg's Arch Pharmacol 345 [Supp12]:R57
Kenakin TP (1984) The classification of drugs and drug receptors in isolated tissues. Pharmacol Rev 36:165–222
Leurs R, Timmerman H (1992) The histamine H3-receptor: A target for developing new drugs. Progr Drug Res 39:127–165
McPherson GA, Molenaar P, Raper C, Malta E (1983) Analysis of dose-response curves and calculation of agonist dissociation constants using a weighted nonlinear curve fitting program. J Pharmacol Methods 10:231–241
Pollard H, Moreau J, Arrang JM, Schwartz JC (1993) A detailed autoradiographic mapping of histamine H3 receptors in rat brain areas. Neuroscience 52:169–189
Schlicker E, Behling A, Lümmen G, Göthert M (1992a) Histamine H3A receptor-mediated inhibition of noradrenaline release in the mouse brain cortex. Naunyn-Schmiedeberg's Arch Pharmacol 345:489–493
Schlicker E, Lümmen G, Behling A, Göthert M (1992b) Inhibition of noradrenaline release via NEM-sensitive H3 receptors in the mouse brain cortex: more marked effect than in the rat brain. Agents Actions (Special Conference Issue):C339–C342
Schwartz JC, Arrang JM, Garbarg M, Pollard H (1990) A third histamine receptor subtype: Characterization, localisation and functions of the H3-receptor. Agents Actions 30:13–23
Taylor SJ, Kilpatrick GJ (1992) Characterization of histamine-H3 receptors controlling non-adrenergic contractions of the guinea pig isolated ileum. Br J Pharmacol 105:667–674
Van der Goot H, Bast A, Timmerman H (1991) Structural requirements for histamine H2 agonists and H2 antagonists. In: Uvnäs B (ed) Histamine and histamine antagonists. Springer, Berlin Heidelberg New York, pp 573–748
Van der Goot H, Schepers MJP, Sterk GJ, Timmerman H (1992) Isothiourea analogues of histamine as potent agonists or antagonists of the histamine H3-receptor. Eur J Med Chem 27:511–518
Van Rossum JM (1963) Cumulative dose-response curves. — II. Technique for the making of dose-response curves in isolated organs and the evaluation of drug parameters. Arch Int Pharmacodyn 143:299–330
West RE, Zweig A, Shih N-Y, Siegel MI, Egan RW, Clark MA (1990) Identification of two H3-histamine receptor subtypes. Mol Pharmacol 38:610–613
Author information
Authors and Affiliations
Additional information
Correspondence to: E. Schlicker at the above address
Rights and permissions
About this article
Cite this article
Kathmann, M., Schlicker, E., Detzner, M. et al. Nordimaprit, homodimaprit, clobenpropit and imetit: affinities for H3 binding sites and potencies in a functional H3 receptor model. Naunyn-Schmiedeberg's Arch Pharmacol 348, 498–503 (1993). https://doi.org/10.1007/BF00173209
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00173209