BACKGROUNDalpha(1)-Acid glycoprotein (AGP) plays a decisive role in the serum protein binding of several drugs.Genetic variants of AGP have different ligand binding properties. The binding of deramciclane (DER), a chiral anxiolytic agent, has been studied on A and F1/S genetic variants of AGP.METHODSThe effects of DER and reference drugs on the binding of specific fluorescent and circular dichroism (CD) probes of AGP were determined. Dicumarol (DIC) binding was measured by CD and equilibrium dialysis.RESULTSDER effectively displaced probes bound to variant A, while it was less effective at displacing probes bound to variant F1/S. DER increased the binding and inverted the induced CD spectrum of DIC in the solution of variant F1/S. This phenomenon could not be brought about by the enantiomer of DER.CONCLUSIONDER has high-affinity binding (K(a)> or =2x10(6) M(-1)) to variant A, while its binding to the variant F1/S is about thirty times weaker. During simultaneous binding of DER and DIC to variant F1/S a ternary complex having about four times higher affinity is formed, in which the opposite chiral conformation of DIC is favored.GENERAL SIGNIFICANCEThe binding interactions found prove that AGP can simultaneously accommodate different ligand molecules. Even weakly bound ligands can provoke unexpected allosteric protein binding interactions.

2010-02-01·Pharmacology Biochemistry and Behavior4区 · 心理学

Deramciclane improves object recognition in rats: Potential role of NMDA receptors

4区 · 心理学

Article

作者: György Lévay ; István Gacsályi ; Gábor Kapus ; Szabolcs Kertész

The cognition-enhancing properties of deramciclane (N,N-dimethyl-2-([(1R,4R,6S)-1,7,7-trimethyl-6-phenyl-6-bicyclo[2.2.1]heptanyl]oxy)ethanamine) and memantine (3,5-dimethyl-tricyclo[3.3.1.1(3,7)]decylamine-3,5-dimethyladamantan-1-amine) were evaluated in the novel object recognition (OR) test in the rat, while their effect in comparison with other N-methyl-D-aspartate (NMDA) receptor blockers such us MK-801 ([+]-5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine maleate) and CPP ([+/-]-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid) on NMDA-evoked spreading depression (SD) was investigated in the chicken retina, in vitro. In the OR test, pretreatment of rats with either deramciclane (30 mg/kg p.o.) or memantine (10 and 30 mg/kg, p.o.) resulted in preference for the novel object, compared to the familiar one, indicating procognitive activity of the compounds. In the in vitro studies memantine (10-30 M), or deramciclane (30-100 M) as well as CPP (0.1-1 M), MK-801 (0.3-1 M), concentration-dependently inhibited NMDA evoked SD. Furthermore, the inhibitory effect of memantine, deramciclane and MK-801 was activity-dependent. These results support the role of NMDA receptors in the procognitive effect of deramciclane.

2008-01-01·Basic & Clinical Pharmacology & Toxicology3区 · 医学

Comparison of the Effects of Deramciclane, Ritanserin and Buspirone on Extracellular Dopamine and Its Metabolites in Striatum and Nucleus Accumbens of Freely Moving Rats

3区 · 医学

Article

作者: Tiina M. Kääriäinen ; Mikko Käenmäki ; Marko Lehtonen ; Pekka T. Männistö ; Jouko Savolainen ; Markus M. Forsberg

Abstract: In the present study, we assessed the effect of single graded doses of a putative anxiolytic compound, the 5‐HT2A/C antagonist, deramciclane fumarate (EGIS‐3886), on the dopamine efflux and metabolism in nucleus accumbens and striatum and thus evaluated the dose window for deramciclane to cause adverse effects related to the brain dopaminergic system. Dual probe in vivo microdialysis in freely moving rats was used to compare the effects of graded doses of deramciclane fumarate (3, 10 and 30 mg/kg), 5‐HT2A/C antagonist ritanserin (1 mg/kg) and a partial 5‐HT1A agonist buspirone hydrochloride (5 mg/kg) on the extracellular levels of dopamine, 3,4‐dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in nucleus accumbens and striatum assayed by high performance liquid chromatography with electrochemical detection. The indirect dopamine agonist, D‐amphetamine sulfate (2 mg/kg), was used as a positive control. Ritanserin, buspirone and deramciclane 3 and 10 mg/kg had no significant effects on the extracellular dopamine levels in either brain area but deramciclane 30 mg/kg significantly increased accumbal dopamine as well as DOPAC and HVA in both brain areas. As expected, the positive control D‐amphetamine significantly increased both striatal and accumbal dopamine levels. The effects of buspirone or the highest deramciclane dose and D‐amphetamine on DOPAC and HVA levels were opposite; buspirone and deramciclane increased while D‐amphetamine decreased the metabolite levels in both brain areas. The results indicate that a single high dose of deramciclane has the neuroleptic‐ or buspirone‐like effect, particularly in mesolimbic regions. There is at least a 5‐fold margin between the anxiolytic and neuroleptic doses of deramciclane in the rat.

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KEGG	Wiki	ATC	Drug Bank
-	德伦环烷	-	DB06512

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适应症	最高研发状态	国家/地区	公司	日期
焦虑症	临床2期	美国	-	-
焦虑症	临床2期	-	Pfizer Inc.	-
焦虑症	临床2期	-	Orion Oyj	-
焦虑症	临床2期	-	Egis Gyógyszergyár Zrt.	-
焦虑症	临床2期	南非	-	-
焦虑症	临床2期	芬兰	Orion Oyj	-
焦虑症	临床2期	欧洲	-	-
癫痫发作	药物发现	匈牙利	Hungarian Academy of Sciences	1989-03-01