Badania analogów kwasów [gamma]-amino i [gamma]-hydroksymasłowego o przewidywanym działaniu przeciwdrgawkowym

• Autorzy: Malawska B.

Warianty tytułu

EN

Searching of [gamma]-amino and [gamma]-hydroxybutyric acid analogs with expected anticonvulsant activity

• Języki publikacji: PL

Abstrakty

EN

In the search for new anticonvulsants, derivatives of a-substituted g-amino-, g-phthalimido-, and g-hydroxybutyric acid such as acids, esters and amides were obtained. Preliminary pharmacological tests, a maximal electroshock (MES) and a subcutaneous metrazole (scMet), and a rotorod toxicity assay for all synthesized compounds were employed. It was shown that a-substituted N-benzylamides of g-hydroxybutyric acid (GHB) were the most potent compounds and possessed anticonvulsant activities in the (MES) screens. The most potent anticonvulsant compounds were a-(benzylamino)- g-hydroxybutyric acid N-benzylamide and N-(2-chlorobenzylamide) with medium effective (ED50) doses 63.0 mg/kg and 54.0 mg/kg, respectively . These compounds were less active then the commonly used anticonvulsants carbamazepine and phenytoin, but had higher activity in the MES screen than sodium valproate. The preliminary biochemical tests suggest that the active amides are acted as an allosteric modulator of the g-aminobutyric acid, GABA-A complex, and have the affinity to voltage sensitive calcium channels (VSCC) receptors. It may be the possible mechanism which mediates the anticonvulsant effect of these compounds. Four series of N-benzylamides of GHB, which contained the N-(4-phenylpiperazine)- (series A), N-(4-benzylpiperazine)- (series B), N-benzylamino-(series C), or N-(2-phenylethylamine)- (series D), group in the a-position of GHB were selected as models to found out the structural elements and/or physicochemical properties responsible for their anticonvulsant action. The lipophilicities of four anticonvulsant active series of compounds were determined by reversed-phase thin-layer chromatography (RM value) . The partition coefficients (log P) of the amides were calculated by use of the Prolog P module of the Pallas system. Comparison of RM and log P enabled calculation of clog P values. It was found that anticonvulsant activity of amides series A-D may be explained on the basis of their lipophilicity. In order to point to some structural features correlating with the MES anticonvulsant activity crystal structure analysis followed by conformational analysis was carried out on two compounds of series A and B. Molecular modelling investigations were carried out using computer program on the representative compounds of series A-D. Based on the pharmacological, physicochemical, rentgenostructural and molecular modelling results the pharmacophore model for anticonvulsant N-substituted amides of GHB was design. In this model, the presence of the N-benzylamide fragment is essential for activity. For amides the further elements are hydrophobic unit (aryl ring) as a distal binding site and H-bond as a donor function. Based on this model new compounds with expected anticonvulsant activity may be design.

Słowa kluczowe

PL

badania farmakologiczne; badania strukturalne; analogi kwasów y-amino i y-hydroksymasłowego

• Wydawca: Polskie Towarzystwo Chemiczne
• Czasopismo: Wiadomości Chemiczne
• Rocznik: 2001
• Tom: [Z] 55, 3-4
• Strony: 377--402
• Opis fizyczny: wykr., bibliogr. 68 poz.

Twórcy

autor

Malawska B.

• Katedra Chemii Farmaceutycznej Collegium Medicum Uniwersytetu Jagiellońskiego 30-688 Kraków, ul. Medyczna 9

Bibliografia

• [1] E. Roberts, T.N. Chase, D.B. Tower (red.), GABA in Nervous System Function, Raven Press, New York 1976.
• [2] P. Krogsgaard-Larsen, B. Frolund, F. Jorgensen, A. Schousboe, J. Med. Chem., 1994, 37, 2489.
• [3] P. K rogsgaard-Larsen, Eur. J. Pharmac. Sciences, 1994, 2, 59.
• [4] W. Löscher, [w:] GABA: Basic Research and Clinical Applications, N.G. Bowery, G. Nistico (red.), Pythagora Press, Rome, 1989, s. 260.
• [5] O. McNamara A.G. Goodman, T.W. Rail, A.S. Nies, P. Taylor, [w:] The Pharmacological Basis of Therapeutics, 9th ed. McGraw-Hill, 1996,461.
• [6] B. Malawska, Wiad. Chem., 1989, 43, 457.
• [7] K. Ossowska, [w:] Receptory. Struktura, charakterystyka, funkcja, J.Z. Nowak, J.B. Zawilska (red.), PWN, Warszawa 1997, 143.
• [8] O.C. Snead, Life Sei., 1977, 20, 1935.
• [9] P. Vayer, P. Mandel, M. Maitre, ibid., 1987, 41, 1547.
• [10] P. Mathivet, R. Bernasconi, J. De Barry, C. Marescaux, H. Bittiger, Eur. J. Pharmacol., 1997, 312, 67.
• [11] O.C. Snead, C.C. Liu, Neuropharmacology, 1993, 32, 401.
• [12] O.C. Snead, Brain Res., 1994, 659, 147.
• [13] P. Banerjee, O.C. Snead, J. Pharmacol. Exp. Ther., 1995, 273, 1534.
• [14] O.C. Snead, Pharmacol. Biochem. and Behav., 1996, 53, 73.
• [15] O.C. Snead, Neuropharmacology, 1996, 35, 359.
• [16] I.O. Edafiogho, K.R. Scott, [w:] Burger’s Medicinal Chemistry and Drug Discovery, V wyd. Therapeutic Agents, red. Wolff M.E. 1996, 3, 175.
• [17] P.N. Patsalos, J.S. Duncan, CNS Drugs, 1994, 2,40.
• [18] A.K. Saxen a, M. Saxena, [w:] Progress in Drug Research, E. Jucker (red.), Birkhauser Verlag, Basel, 1995, 44, 185.
• [19] B. Malawska, M. Gorczyca, W. Wieczorek, J. Cryst. Spectr. Res., 1990, 20, 139.
• [20] D. Malec, J. Modzelewski, B. Malawska, M. Gorczyca, Pol. J. Pharmacol. Pharm., 1990, 42, 491.
• [21] W. Wieczorek , B. Malawska, J. Cryst. Spectr. Res., 1992, 22, 157.
• [22] W. Wieczorek , B. Malawska, J. Chem. Cryst., 1994, 24, 521.
• [23] N.P. Gensman tel, [w:] Medicinal Chemistry, Principles and Practice, F.D. King (red.), The Royal Society of Chemistry, 1994, 98.
• [24] B. Malawska, S. Gobaille, Pharmazie, 1995, 50, 390.
• [25] B. Malawska, A. Zejc, ibid., 1995, 50. 722.
• [26] N. Ono, T. Yamada, T. Saito, K. Tanaka, A. Kaji, Bull. Chem. Soc. Jpn., 1978, 51, 2401.
• [27] P. Chevallet, P. Garrouste, B. Malawska, J. Martinez, Tetrahedron Lett., 1993, 34, 7409.
• [28] B. Malawska, L. Antkiewicz-Michaluk, Die Pharmazie, 1999, 54, 239.
• [29] B. Malawska, K. Kulig, L. Antkiewicz-Michaluk , R. Porter, A. Misra, I.A. Cliffe, Arch. Pharm. Pharm. Med. Chem., 1999, 332,167.
• [30] B. Castro, J.R. Dormoy, G. Evin, C. Selve, Tetrahedron Lett., 1975,14, 1219.
• [31] Z.J. Kamiński, Synthesis, 1987, 917.
• [32] M. Bodanszky, A. Bodanszky, The Practice of Peptide Synthesis, Springer-Verlag Berlin-Heidelberg-New York-Tokyo 1984, 149.
• [33] B. Malawska, K. Kulig, M. Ciechanowicz-Rutkowska, Arch. Pharm. Pharm. Med. Chem., 1997,330, 91.
• [34] R.J. Porter, J.J. Cereghino, G.D. Gladding, B.J. Hessie, H.J. Kupferberg, B. Scoville , B.G. White, Antiepileptic drug development program, Cleveland Clin. Q, 1984, 51,29.

Uwagi

PL

Opracowanie rekordu ze środków MEiN, umowa nr SONP/SP/546092/2022 w ramach programu "Społeczna odpowiedzialność nauki" - moduł: Popularyzacja nauki i promocja sportu (2022-2023).