Studies of the side chain cleavage of deramciclane in rats with radiolabelled compounds
Introduction
Deramciclane is a novel non-benzodiazepine type of anxiolytic compound, which in a therapeutic dose range lacks the potentiating effect of ethanol, i.e. muscle relaxant activity and sedative properties (Gacsályi et al., 1988, Gacsályi et al., 1996). A relatively strong plasma protein (albumin, acidic glycoprotein) binding of deramciclane was found in different species (Visy et al., 1996).
Receptor binding studies revealed its high affinity to 5-HT2A and 5-HT2C receptor subfamilies (Gacsályi et al., 1996, Gacsályi et al., 1997, Pälvimäki et al., 1998). Several pharmacokinetic studies were carried out earlier on animals (rat, dog, rabbit) and on humans, and significant species variations were found in the pharmacokinetic properties of deramciclane (Kanerva et al., 1998a, Kanerva et al., 1998b, Kanerva et al., 1999a, Kanerva et al., 1999b, Klebovich et al., 1998, Hazai et al., 1999, Balogh Nemes et al., 2000).
Our previous pharmacokinetic studies with deramciclane-ethyl-14C revealed that the 14C-label of the side chain can be detected both in plasma and in the tissues of rats several days after drug administration (Magyar et al., 1998). By contrast, using deramciclane-phenyl-14C or deramciclane-camphor-3H radioisomers, labelling the core of the molecule, almost the total amount of radioactivity left the body within 24 h (Lengyel et al., 1998a). The dissociation observed in the radioactivities (labelling the side chain and the core of the molecule by 14C and 3H, respectively), indicates an intensive cleavage of the compound at the ether bond. The intensity of the process depends on species, being ∼30–40% in rats and dogs. According to our present studies, the rate of the side chain cleavage is less intensive in humans (unpublished observation). The persisting tissue levels of radioactivity derived from the side chain prompted us to study its fate in the body.
In our present investigations rats were treated orally with a mixture of alternatively labelled radioisomers of deramciclane and 14C-DMAE, which provided a new sensitive method to study the fate of the side chain in rats.
Section snippets
Chemicals
Deramciclane fumarate (EGIS-3886; CAS 120-444-78-8; (1R,2S,4R)-(−)-N,N-dimethyl-2-{(1,7,7-trimethyl-2-phenylbicyclo-[2,2,1]-hept-2-yl)oxi}ethaneamine-2-(E)-butendioate (1:1)) was synthesised by EGIS Pharmaceuticals (Budapest, Hungary). All other chemicals used in these studies were purchased from Reanal (Budapest, Hungary) and Merck (Darmstadt, Germany); their quality was of analytical or chromatographic grade.
Radioactive substances
Deramciclane-phenyl-14C (specific activity: 1.37 GBq/mmol), deramciclane-camphor-3H
Results
The time related changes in plasma concentrations of rats treated with the mixture of the radioisomers of deramciclane-camphor-3H and deramciclane-ethyl-14C, or deramciclane-camphor-3H and DMAE-14C, or deramciclane-phenyl-14C and calculated on the basis of total radioactivity are presented in Fig. 2. A striking difference was found between the plasma levels of DMAE and the radioisomers labelled at the core of deramciclane. The plasma level of DMAE-14C could be measured during the whole
Discussion
Our earlier and present pharmacokinetic studies with deramciclane-phenyl-14C, camphor-3H and -ethyl-14C radioisomers indicated that in rats the side chain was cleaved at the ether bond and at least a small fraction of the side chain residue eliminated at a lower rate compared to the core of the molecule (Lengyel et al., 1998b, Magyar et al., 1998; Fig. 1). The cleavage of the ether bridge by the microsomal enzymes results in the formation of aldehyde, which can preferentially be further
Acknowledgements
The authors wish to thank to Maria Knippel for her technical help in preparing the manuscript. Special thanks are due to Ágota Walter and Tibor Nagy for their careful work during the study.
References (23)
- et al.
Oral, intraperitoneal, intravenous pharmacokinetics of deramciclane and its N-desmethyl metabolite in rat
J. Pharm. Pharmacol.
(2000) - et al.
The use of Wittenborn psychiatric rating scales in geriatric psychiatry. Results of a double blind study with cyprodenate and placebo
Arzneim.-Forsch. Drug Res.
(1972) - et al.
Symptomatic postoperative Korsakoff’s syndrome caused by an aneurysm of the anterior communicating artery
Evol. Psychiatr.
(1969) - et al.
Pharmacokinetic study of maleate acid of 2-(N,N-dimethylaminoethanol-14C1)-cyclohexylpropionate (cyprodenate) and of N,N-dimethylaminoethanol-14C1 in animals
Arzneim.-Forsch. Drug Res.
(1975) - et al.
Psychopharmacology of a new anxiolytic agent EGIS-3886
Pharm. Res. Commun.
(1988) - et al.
Different antagonistic activity of deramciclane (EGIS-3886) on peripheral and central 5-HT2 receptors
Pharm. Pharmacol. Lett.
(1996) - et al.
Receptor binding profile and anxiolytic activity of deramciclane (EGIS-3886) in animal models
Drug Dev. Res.
(1997) - et al.
The comparative distribution of 14C-labelled 2-dimethylaminoethanol and choline in the mouse
J. Pharmacol. Exp. Ther.
(1958) - et al.
Whole body autoradiography and quantitative organ-level distribution study of deramciclane in rats
J. Pharm. Pharmacol.
(1999) - et al.
Pharmacokinetics of deramciclane in dogs after single oral and intravenous dosing and multiple oral dosing
Biopharm. Drug Dispos.
(1998)
Different absorption profile of deramciclane in man and in dog
J. Pharm. Pharmacol.
Cited by (5)
Design, synthesis, and biological evaluation of a 1α,25-dihydroxy-19- norvitamin D<inf>3</inf> analogue with a frozen A-ring conformation
2007, Journal of Medicinal ChemistryBiotransformation of deramciclane in primary hepatocytes of rat, mouse, rabbit, dog, and human
2005, Drug Metabolism and DispositionSynthesis of deramciclane* labeled with tritium in various positions
2005, Journal of Labelled Compounds and Radiopharmaceuticals