Screening for new 5HT1A receptor agonists and antagonists

Screening for new 5HT1A receptor agonists and antagonists Zdzis³aw Chilmoñczyk1, Andrzej Mazurek1, Franciszek Pluciñski1, Aleksander P. Mazurek1, Andrzej J. Bojarski2 National

Medicines Institute, Che³mska 30/34, 00-725 Warszawa, Poland; Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, Smêtna 12, 31-343 Kraków, Poland

5-HT1A receptor has been the subject of several studies since it was shown to be involved in various physiological functions like sleep, appetite and pathological status such as anxiety and depression [Barnes NM and Sharp T, Neuropharmacology, 1999]. In our present study we used similarity-based virtual screening (VS) and VS by docking to identify new 5-HT1A receptor agonists and antagonists. The main steps of VS protocol were ADME/Tox filter, three-dimensional pharmacophore searches and docking protocol. As an input 84 well-known 5-HT1A receptor ligands were used which were subsequently divided into agonists (50) and antagonists (34). In each group several structural classes (arylpiperazine derivatives, tricyclic psychotropic agents, serotonin derivatives etc.) were distinguished. 3D pharmacophores consisting of H-bond

acceptor, H-bond donor, hydrophobic aromatic, hydrophobic aliphatic, positive ion and ring aromatic were constructed for both agonists and antagonists. A library consisted of approx. 800 000 drug-like compounds from Enamine Screening Collection has been screened. The library has been sieved with ADME/ tox filter consisting of predicted central nervous system activity, octanol/water partition coefficient, apparent Caco-2 cell permeability, brain/blood partition coefficient and human oral absorption (Schrödinger software) followed by pharmacophoric structural elements matching resulting in candidates for agonists and antagonists selection. This study was partly supported by a grant PNRF-103-AI-1/07 from Norway through the Norwegian Financial Mechanism.

Influence of caffeine on the protective potency of antiepileptic drugs in the 6 Hz psychomotor seizure model in mice Magdalena Chroœciñska-Krawczyk1, Magdalena Wa³ek1, Bo¿ydar Tylus1, Stanis³aw J. Czuczwar1,2 Department

of Pathophysiology, Medical University of Lublin, Jaczewskiego 8, 20-090 Lublin, Poland; Department of Physiopathology, Institute of Agricultural Medicine, Jaczewskiego 2, 20-950 Lublin, Poland

The aim of this study was to determine the influence of caffeine (administered chronically or acutely) on the protective activity of some newer antiepileptic drugs (AEDs): oxcarbazepine (OXC), levetiracetam (LEV) and lamotrigine (LTG) in the 6 Hz psychomotor seizure model in mice. Caffeine (1,3,7-trimethylxantine) is the most commonly ingested stimulant all over the world. Experimental studies have demonstrated that caffeine, in relatively low (non-convulsive doses), reduces the protective effects of classic antiepileptic drugs against maximal electroshock- and pentylenetetrazol-induced seizures [Kleinrok and Czuczwar, Pharmacol Res, 1990]. The experiments were con38

Pharmacological Reports, 2010, 62, suppl.

ducted on male Swiss mice. Topical anaesthetic (0.5% tetracaine hydrochloride) was applied to the cornea before corneal stimulation (0.2 ms duration pulses at 6 Hz for 3 s) administered by constant-current device (ECT Unit 57800; Ugo Basile, Comerio, Italy). The tested drugs and caffeine were administered intraperitoneally. The anticonvulsant activity of the AEDs was determined by evaluating the respective ED50 values, i.e., the calculated doses required to block seizures in 50% of the tested animals. Caffeine administered chronically (twice daily for 15 days) and acutely, at doses 23.1 and 46.2 mg/kg, reduced the protective potency of LEV. That of OXC was decreased by caffeine