Novel agonists of benzodiazepine receptors: Design, synthesis, binding assay and pharmacological evaluation of 1,2,4-triazolo[1,5-a]pyrimidinone and 3-amino-1,2,4-triazole derivatives
Graphical abstract
Based on SAR of benzodiazepine receptor agonists, novel scaffold are introduced as hypnotic and anticonvulsant agents without any impairing effect on memory and learning.
Introduction
Agonists of benzodiazepine (BZD) receptor, are extensively used in the treatment of epilepsy, anxiety, muscle cramps and sleep disorders.1 The pharmacological effects of BZDs result from their affinity for a specific binding site on the GABAA receptors, known as the BZD receptor.2, 3, 4 BZD receptor agonists modulate the allosteric GABA binding site and increase the opening of a selective chloride ion channel that causes hyperpolarization of the post-synaptic membrane.1 Since BZDs have some adverse effects,5 development of the novel BZD receptor agonists is still continued and a great deal of attention. Among all pharmacophores proposed for binding to the BZD receptors, an aromatic ring and a coplanar proton-accepting group in suitable distance are essential for interaction with the receptor. In addition, binding to the receptor could be potentiated by second out-of-plane aromatic ring.6, 7 According to this structure–activity relationship (SAR) and in continuance of our previous studies on some simple non-rigid derivatives with five member heterocycle rings such as triazoles, oxadiazoles, and thiadiazoles,6, 8, 9, 10, 11, 12, 13, 14, 15, 16 We designed some structures with all suggested requirements (Fig. 1) and performed conformational analysis followed by superimposition of energy minima conformers of the designed compounds on estazolam, a known BZD agonist to confirm whether they could mimic the structure of a BZD agonist. The synthesized compounds were evaluated for their in vitro affinity to BZD receptor by radioligand receptor binding assay. The compound, which had the best affinity to BZD receptor, was studied in vivo for its pharmacological effects. The anticonvulsant action was determined using pentylenetetrazole (PTZ)-induced lethal convulsion and maximal electroshock (MES) tests. Mouse learning and memory impairment was evaluated by passive avoidance test and the hypnotic effect was measured through potentiating of pentobarbital sleeping time model. Finally, to confirm the mode of action of the synthesized compound, the effect of flumazenil, a BZD receptor antagonist, on the pharmacological activity of the compounds was determined.
Section snippets
Conformational analysis
Conformational analysis of the designed compounds and estazolam were performed through MMX force field method followed by AM1 calculation. Figure 2 represents the superimposition of the energy minima conformer of the compound 4c on estazolam as a known BZD agonist. Obviously, the main BZD pharmacophores, aromatic rings and proton accepting groups are in the same orientation which means the designed compound could well mimic the agonistic shape of BZD ligands.
Chemistry
The designed compounds were
Conclusions
In summary, the derivatives of 1,2,4-triazolo[1,5-a]pyrimidinone and 1,2,4-triazole-3-amine as novel BZD agonists were investigated. Most of the novel synthesized compounds showed better affinity for CBR than diazepam in radioligand binding assay. Compound 4c with the highest affinity for CBR was evaluated in biological assay. This compound revealed considerable hypnotic and weak anticonvulsant activity beside no impairment on learning and memory. Since most of the potent BZD agonists affect
Calculations
Conformational analysis of the synthesized compounds and estazolam were performed preliminarily through MMX force field method followed by AM1 calculation implemented in HyperChem8 software (Hypercube, Inc.). The global energy minima conformers of the designed compounds on corresponding conformer of estazolam molecule, a known BZD agonist, were superimposed.
Materials and instrumentation
Melting points (Mp) were determined using the Electrothermal 9100 apparatus and are uncorrected. Infrared spectra were acquired on a
Acknowledgments
This work was supported by grant from the Research Council of Shahid Beheshti University of Medical Sciences and Iran National Science Foundation (INSF). We would like to acknowledge the Radiopharmacy Laboratory, School of Pharmacy, Shahid Beheshti University of Medical Sciences for radioligand receptor binding studies.
References and notes (33)
- et al.
Bioorg. Med. Chem.
(2007) - et al.
Bioorg. Med. Chem. Lett.
(2005) - et al.
Eur. J. Pharmacol.
(1996) - et al.
Trends Pharmacol. Sci.
(1995) - et al.
Bioorg. Med. Chem.
(2003) - et al.
Bioorg. Med. Chem.
(2003) - et al.
Bioorg. Med. Chem. Lett.
(2004) - et al.
Bioorg. Med. Chem. Lett.
(2005) - et al.
Nucl. Med. Biol.
(2013) - et al.
Bioorg. Med. Chem.
(2008)
Anal. Biochem.
Eur. J. Med. Chem.
Acta Chim. Slovenica
DARU J. Pharm. Sci.
Chem. Pharm. Bull.
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