Last update 01 Nov 2024

AChE x H2 receptor

Last update 01 Nov 2024

Basic Info

Related Targets

AChEH2 receptor

Drugs associated with AChE x H2 receptor

KW-5092

Target

AChE x H2 receptor

Mechanism

AChE inhibitors [+1]

Active Org.-

Originator Org.

Kyowa Kirin Co., Ltd.

Active Indication-

Inactive Indication

Gastroesophageal Reflux

Drug Highest PhaseDiscontinued

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with AChE x H2 receptor

100 Translational Medicine associated with AChE x H2 receptor

0 Patents (Medical) associated with AChE x H2 receptor

Literatures (Medical) associated with AChE x H2 receptor

01 Oct 2016·Physiology & BehaviorQ3 · MEDICINE

The dual-acting AChE inhibitor and H3 receptor antagonist UW-MD-72 reverses amnesia induced by scopolamine or dizocilpine in passive avoidance paradigm in rats

Q3 · MEDICINE

Article

Author: Decker, Michael ; Pockes, Steffen ; Khan, Nadia ; Sadek, Bassem ; Darras, Fouad H

Both the acetylcholine esterase (AChE) and the histamine H3 receptor (H3R) are involved in the metabolism and modulation of acetylcholine release and numerous other centrally acting neurotransmitters. Hence, dual-active AChE inhibitors (AChEIs) and H3R antagonists hold potential to treat cognitive disorders like Alzheimer's disease (AD). The novel dual-acting AChEI and H3R antagonist 7-(3-(piperidin-1-yl)propoxy)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one (UW-MD-72) shows excellent selectivity profiles over the AChE's isoenzyme butyrylcholinesterase (BChE) as well as high and balanced in-vitro affinities at both AChE and hH3R with IC50 of 5.4μM on hAChE and hH3R antagonism with Ki of 2.54μM, respectively. In the current study, the effects of UW-MD-72 (1.25, 2.5, and 5mg/kg, i.p.) on memory deficits induced by the muscarinic cholinergic antagonist scopolamine (SCO) and the non-competitive N-methyl-d-aspartate (NMDA) antagonist dizocilpine (DIZ) were investigated in a step-through type passive avoidance paradigm in adult male rats applying donepezil (DOZ) and pitolisant (PIT) as reference drugs. The results observed show that SCO (2mg/kg, i.p.) and DIZ (0.1mg/kg, i.p.) significantly impaired learning and memory in rats. However, acute systemic administration of UW-MD-72 significantly ameliorated the SCO- and DIZ-induced amnesic effects. Furthermore, the ameliorating activity of UW-MD-72 (1.25mg/kg, i.p.) in DIZ-induced amnesia was partly reversed when rats were pretreated with the centrally-acting H2R antagonist zolantidine (ZOL, 10mg/kg, i.p.), but not with the CNS penetrant H1R antagonist pyrilamine (PYR, 10mg/kg, i.p.). Moreover, ameliorative effect of UW-MD-72 (1.25mg/kg, i.p.) in DIZ-induced amnesia was strongly reversed when rats were pretreated with a combination of ZOL (10mg/kg, i.p.) and SCO (1.0mg/kg, i.p.), indicating that these memory enhancing effects were, in addition to other neural circuits, observed through histaminergic H2R as well as muscarinic cholinergic neurotransmission. These results demonstrate the ameliorative effects of UW-MD-72 in two in-vivo memory models and provide evidence for the potential of dual-acting AChEI and H3R antagonists to treat cognitive disorders.

01 Mar 1995·Bioorganic & Medicinal ChemistryQ3 · MEDICINE

Synthesis of 2-imidazolidinylidene propanedinitrile derivatives as stimulators of gastrointestinal motility—III

Q3 · MEDICINE

Article

Author: Ishii, Akio ; Nonaka, Hiromi ; Sasho, Setsuya ; Obase, Hiroyuki ; Yoshizaki, Rika ; Ichikawa, Shunji ; Kitazawa, Takio ; Shuto, Katsuichi

Recently, we reported that a ranitidine derivative 2 (fumarate: KW-5092), which had a 2-imidazolidinylidene propanedinitrile moiety (A), showed potent gastrointestinal motility enhancing activity. We have also found that introduction of substituents such as benzyl or 4-fluorobenzyl (i.e., giving 3 or 4) at the N-3 position of the moiety (A) significantly increased this activity. In this study, novel 2-imidazolidinylidene propanedinitrile derivatives possessing a thioether 5-15 were prepared and evaluated for in vitro assays; acetylcholinesterase (AChE) inhibitory activity and potentiating action on electrically induced contractions of guinea pig ileum. Compound 5, in which a nitrogen atom of compound 2 was replaced by a sulfur atom, was more potent than 2 in these tests. Also, in a series of thioether derivatives, introduction of substituents at the N-3 position of the 2-imidazolidinylidene propanedinitrile moiety markedly influenced both activities. In particular, compounds 12 and 13, which showed an excellent potency during in vitro study (AChE IC50 = 3.6 and 2.7 nM; ES. EC30 = 2.1 and 2.5 nM, respectively), were found to be more active in the enhancement of gastrointestinal motility in anesthetized rabbits than their corresponding parent compounds 3 and 4, respectively. In addition, compounds 12 and 13 showed lower affinity for the histamine H2-receptor than ranitidine. Therefore, these compounds may be potent and selective stimulators of gastrointestinal motility.

01 Oct 1994·Bioorganic & Medicinal ChemistryQ3 · MEDICINE

Synthesis of 2-imidazolidinylidene propanedenitrile derivatives as stimulators of gastrointestinal motility—II

Q3 · MEDICINE

Article

Author: Yokoyama, Toshihide ; Kitazawa, Takio ; Sasho, Setsuya ; Obase, Hiroyuki ; Harakawa, Hiroyuki ; Kishibayashi, Nobuyuki ; Yoshizaki, Rika ; Ichikawa, Shunji ; Nonaka, Hiromi

In a previous paper, we reported that a novel ranitidine derivative 2 (fumarate: KW-5092), which had a 2-imidazolidinylidene propanedinitrile moiety (A), showed potent gastrointestinal motility enhancing activity. In order to obtain more potent gastrointestinal motility enhancing agents than compound 2 and to examine the effects of various substituents both at a nitrogen atom (B) in the 2-imidazolidinylidene propanedinitrile moiety and a basic nitrogen atom (C), compounds 5-29 were synthesized and evaluated for acetylcholinesterase (AChE) inhibitory activity and potentiating action on electrically stimulated contractions of guinea pig ileum. Introduction of alkyl, benzyl, aryl or acyl groups to the nitrogen (B) or (C), remarkably influenced both activities. Among these, compounds 14 and 15 showed more potent AChE inhibitory activity (IC50 = 6.7, 6.8 nM, respectively) than compound 2 and were active in potentiating action on the ileal contraction (EC30 = 9.5, 11 nM, respectively) together with a negligible histamine H2-receptor blocking property. Furthermore, these compounds were found to be more effective in the enhancement of gastrointestinal motility in anesthetized rabbits than compound 2.

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