Chae Hee Kang

Erysodine, a competitive antagonist at neuronal nicotinic acetylcholine receptors

Erysodine, an erythrina alkaloid related to dihydro-beta-erythroidine, was found to be a more potent inhibitor of [3H]cytisine binding at neuronal nicotinic acetylcholine receptors but a less potent inhibitor of [125I]alpha-bungarotoxin binding at muscle-type nicotinic acetylcholine receptors than dihydro-beta-erythroidine. Erysodine was a competitive, reversible antagonist of (-)-nicotine-induced dopamine release from striatal slices and inhibited (-)-nicotine-induced 86Rb+ efflux from IMR-32 cells. Erysodine was equipotent with dihydro-beta-erythroidine in the dopamine release assay but 10-fold more potent in the 86Rb+ efflux assay, suggesting differential subtype selectivity for these two antagonists. Erysodine, systemically administered to mice, entered the brain and significantly attentuated nicotines hypothermic effects and its anxiolytic-like effects in the elevated plus-maze test. There was greater separation between antagonist and toxic doses for erysodine than for dihydro-beta-erythroidine, perhaps because of erysodines greater selectivity for neuronal receptors. In rats, erysodine prevented both the early developing decrease and the late-developing increase in locomotor activity produced by (-)-nicotine. The potent and competitive nature of erysodines antagonism together with its ability to enter the brain after systemic administration suggest that erysodine may be a useful tool in characterizing neuronal nicotinic acetylcholine receptors.

Differential in vivo effects of H3 receptor ligands in a new mouse dipsogenia model.

The selective H(3) receptor agonist (R)-alpha-methylhistamine [(R)-alpha-MeHA] stimulates drinking in the adult rat. In the present study, we investigated the role of the H(3) receptor in mediating this behavior in a new dipsogenia model using the CD-1 mouse. In addition, the putative inverse agonists ciproxifan, thioperamide and clobenpropit; the reported antagonist (1R,2R)-4-[2-(5,5-dimethylhex-1-ynyl)cyclopropyl]imidazole (GT-2331); and the putative neutral antagonist/weak partial agonist proxyfan were evaluated for possible differences in pharmacological activity in this new model. Water intake increased over baseline in a dose-related manner following intraperitoneal administration of 80, 160 or 240 micromol/kg (R)-alpha-MeHA, but this effect was dependent on age (P30<P60<P80=P120). [3H]-N-alpha-methylhistamine binding studies showed no change in H(3) receptor density for the whole mouse brain at these ages. All subsequent studies employed P80 mice dosed with 240 micromol/kg (R)-alpha-MeHA. Ciproxifan (0.001-30 micromol/kg), thioperamide (0.01-10 micromol/kg), clobenpropit (0.1-30 micromol/kg) and GT-2331 (0.03-10 micromol/kg) attenuated drinking dose-dependently, blocking the response completely at the highest doses in each case. In contrast, proxyfan (0.001-10 micromol/kg) only partially attenuated drinking elicited by (R)-alpha-MeHA: coadministration of proxyfan and ciproxifan resulted in an attenuation of ciproxifans effects. This new dipsogenia model provides the first in vivo behavioral evidence for possible pharmacological differences between three putative H(3) receptor inverse agonists, GT-2331 and proxyfan.

Synthesis and evaluation of potent pyrrolidine H3 antagonists

Abstract The synthesis and biological evaluation of novel antagonists of the rat H 3 receptor are described. These compounds differ from prototypical H 3 antagonists in that they do not contain an imidazole moiety, but rather a substituted aminopyrrolidine moiety. A systematic modification of the substituents on the aminopyrrolidine ring was performed using pre-formatted precursor sets, where applicable, to afford several compounds with high affinity and selectivity for the H 3 receptor.

Differential activation of dual signaling responses by human H1 and H2 histamine receptors.

Abstract Stimulation of human H1 and H2‐histamine receptors (HRs) primarily activates signaling pathways to increase intracellular calcium [Ca2+]i and cyclic AMP (cAMP), respectively. Activation of H2‐HR in human embryonic kidney (HEK) cells by histamine and dimaprit increases both cAMP formation and [Ca2+]i, as determined by cAMP‐scintillation proximity assays and fluorescence imaging plate reader (FLIPR) assays. In HEK cells expressing relatively high levels of H2‐HR (Bmax = 26 pmol/mg protein), histamine and dimaprit are full agonists in eliciting cAMP responses with pEC50 values of 9.30 and 7.72 that are 1000‐fold more potent than their respective pEC50 values of 6.13 and 4.91 for increasing [Ca2+]i. The agonist potencies decrease for both responses at lower H2‐HR density (5 pmol/mg protein) and dimaprit exhibits partial agonist behavior for the [Ca2+]i response. The inverse agonists ranitidine and cimetidine more potently inhibit cAMP production in the higher expressing H2‐HR line. Histamine also activated both signaling pathways via human H1‐HRs highly expressed (Bmax = 17 pmol/mg protein) in HEK cells, with a 1000‐fold greater potency for [Ca2+]i vs. cAMP responses (pEC50 = 7.86 and 4.82, respectively). These studies demonstrate a markedly different potency for activation of multiple signaling pathways by H1‐ and H2‐HRs that may contribute to the selectivity of histamine responses in vivo.

D-alanine piperazine-amides: novel non-imidazole antagonists of the histamine H3 receptor

Histamine exerts a neurotransmitter function in the periphery and central nervous system (CNS) through its action at four histamine receptor subtypes: H1, H2, H3 and H4 [1]. The H3 receptor is present in highest concentrations in the CNS. The H3 autoreceptor modulates the amount of histamine released from histaminergic neurons, H3 receptors are also present as heteroreceptors in other neurotransmitter systems and may therefore be useful targets for drug treatment for central nervous system disorders such as attention-deficit disorder, Alzheimer’s disease narcolepsy, epilepsy or schizophrenia [2].