Structure–Activity Characterization of an H2-Receptor Antagonist, 3-Amino-4-[4-[4-(1-piperidinomethyl)-2-pyridyloxy]-cis-2-butenylamino]-3-cyclobutene-1,2-dione Hydrochloride (IT-066), Involved in the Insurmountable Antagonism against Histamine-Induced Positive Chronotropic Action in Guinea Pig Atria

Kijima, Haruko; Isobe, Yoshihiko; Muramatsu, Makoto; Yokomori, Sadakazu; Suzuki, Muneyasu; Higuchi, Shohei

doi:10.1016/s0006-2952(97)00416-4

Cited by 13 publications

(13 citation statements)

References 10 publications

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“…The current set of experiments was performed at 25 °C, making LUF6632 dissociate faster (RT = 6.8 min, Table 2) from the receptor with no substantial p K i shift in affinity at the two incubation times. Similar experiments on other GPCRs, such as CB 1 cannabinoid receptor [32, 33] and histamine H 2 receptor [34], demonstrated that the covalent interaction between the ligand and the receptor resulted in a time-dependent affinity change.…”

Section: Discussionmentioning

confidence: 59%

A covalent antagonist for the human adenosine A2A receptor

Yang

Guo

Michiels

et al. 2016

Purinergic Signalling

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The structure of the human A2A adenosine receptor has been elucidated by X-ray crystallography with a high affinity non-xanthine antagonist, ZM241385, bound to it. This template molecule served as a starting point for the incorporation of reactive moieties that cause the ligand to covalently bind to the receptor. In particular, we incorporated a fluorosulfonyl moiety onto ZM241385, which yielded LUF7445 (4-((3-((7-amino-2-(furan-2-yl)-[1, 2, 4]triazolo[1,5-a][1, 3, 5]triazin-5-yl)amino)propyl)carbamoyl)benzene sulfonyl fluoride). In a radioligand binding assay, LUF7445 acted as a potent antagonist, with an apparent affinity for the hA2A receptor in the nanomolar range. Its apparent affinity increased with longer incubation time, suggesting an increasing level of covalent binding over time. An in silico A2A-structure-based docking model was used to study the binding mode of LUF7445. This led us to perform site-directed mutagenesis of the A2A receptor to probe and validate the target lysine amino acid K153 for covalent binding. Meanwhile, a functional assay combined with wash-out experiments was set up to investigate the efficacy of covalent binding of LUF7445. All these experiments led us to conclude LUF7445 is a valuable molecular tool for further investigating covalent interactions at this receptor. It may also serve as a prototype for a therapeutic approach in which a covalent antagonist may be needed to counteract prolonged and persistent presence of the endogenous ligand adenosine.Electronic supplementary materialThe online version of this article (doi:10.1007/s11302-016-9549-9) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 59%

A covalent antagonist for the human adenosine A2A receptor

Yang

Guo

Michiels

et al. 2016

Purinergic Signalling

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“…6). Several reportshaveshown previouslythat the irreversibler eceptor antagonists or the irreversiblee nzyme inhibitors generallys howat ime-dependent inhibitorya ction in vitro (24)(25)(26). Thus,the time-related antiplateletaction of the active metabolite of CS-747would provide additional evidencefor the irreversiblea ntiplatelet activity of CS-747 taking place throught he formation of ad isulfide bondb etween the active metabolite and the P2Y 12 receptor.However,itshould be noted that the time-related inhibition observed in vitro does not necessarilyl ead to as lowo nset of action in vivo as indicated by the rapidonset of action after oraladministration of CS-747 to rats (13).Another contributing factor forthe time-dependent antiplatelet activity might be competition with plasma protein binding.…”

Section: Discussionmentioning

confidence: 96%

Stereoselective inhibition of human platelet aggregation by R-138727, the active metabolite of CS-747 (Prasugrel, LY640315), a novel P2Y12 receptor inhibitor

Hasegawa¹,

Sugidachi²,

Ogawa³

et al. 2005

Thromb Haemost

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CS-747 (Prasugrel, LY640315) is a thienopyridine antiplatelet prodrug that is metabolized to the thiol-containing active metabolite R-138727,which binds to and irreversibly inhibits the platelet P2Y12ADP receptor. R-138727 is composed of 4 stereo-isomers, (R, S)-, (R, R)-, (S, S)-, and (S, R)-isomers (the first letter for the configuration of a chiral center at the sulfur-bearing position and the second for that at the benzylic position). In the present study, we determined the stereoselectivity of P2Y12 antagonist effects by assessing the antagonism of the [3H]-2-MeS-ADP that binds to human P2Y12 receptors expressed in Chinese hamster ovary cells as an affinity assay, and by the inhibition of ADP-induced aggregation of washed human platelets as a functional assay. R-138727 and its 2 components, R-99224, a mixture of (R, S)- and (S, R)-isomers and R-100364, a mixture of (R, R)- and (S, S)-isomers, inhibited [3H]-2-MeS-ADP binding and platelet aggregation. The rank order of potency of these compounds were identical in both assays: R-99224>R-138727>> R-100364. Inhibition of ADP-induced platelet aggregation by R-138727 and R-99224 was concentration- and time-related. In experiments using the 4 single stereo-isomers, all isomers inhibited ADP-induced platelet aggregation, but the (R, S)-isomer was found to be the most potent, followed by the (R, R)-isomer. These in vitro studies indicate that R- 138727 is an effective antagonist of P2Y12 and potent inhibitor of ADP-induced platelet aggregation, and that these antiplatelet activities of R-138727 are largely dependent on its (R, S)-isomer. This suggests that the (R)-configuration of the reactive thiol group of the active metabolite of CS-747 is critical for P2Y12 and platelet inhibitory activities.

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“…52 Independently, H 2 antagonists incorporating squaramides were investigated by groups from Sankyo 95, Taisho pharmaceuticals 63 and Bristol-Myers-Squibb 62. 53,54 Both Pibutidine 63 and BMY-25368 62 were advanced into clinical studies (Fig. 33).…”

Section: Squaramides As Neutral Isosteres Of Ureas Guanidines and Cya...mentioning

confidence: 99%

Squaramides: physical properties, synthesis and applications

2011

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Squaramides are remarkable four-membered ring systems derived from squaric acid that are able to form up to four hydrogen bonds. A high affinity for hydrogen bonding is driven through a concomitant increase in aromaticity of the ring. This hydrogen bonding and aromatic switching, in combination with structural rigidity, have been exploited in many of the applications of squaramides. Substituted squaramides can be accessed via modular synthesis under relatively mild or aqueous conditions, making them ideal units for bioconjugation and supramolecular chemistry. In this tutorial review the fundamental electronic and structural properties of squaramides are explored to rationalise the geometry, conformation, reactivity and biological activity.

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Cited by 13 publications

References 10 publications

A covalent antagonist for the human adenosine A2A receptor

A covalent antagonist for the human adenosine A2A receptor

Stereoselective inhibition of human platelet aggregation by R-138727, the active metabolite of CS-747 (Prasugrel, LY640315), a novel P2Y12 receptor inhibitor

Squaramides: physical properties, synthesis and applications

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