Abstract
Glycine, in addition to GABA, is one of the most important neurotransmitter amino acids. The described structure pharmacokinetic pharmacodynamic relationships (SPPR) study explored the possibility of utilizing phthaloyl derivatives of glycine as new antiepileptics. This was carried out by investigating the pharmacokinetics and pharmacodynamics (anticonvulsant activity and neurotoxicity) of the following four phthalimide derivatives: phthaloyl glycine, phthaloyl glycinamide, N,N-diethyl phthaloyl glycinamide and N,N-diisopropyl phthaloyl glycinamide. Phthaloyl glycine did not demonstrate anticonvulsant activity, possibly because of its poor pharmacokinetics, high clearance, low volume of distribution and short half life. The three glycinamide derivatives showed anticonvulsant activity and had better pharmacokinetic profiles, longer half life and mean residence time, than phthaloyl glycine. Phthaloyl glycinamide was more potent than one of the major antiepileptic agents— valproic acid and showed a better margin between activity and neurotoxicity. The four investigated phthaloyl glycine derivatives did not operate as chemical drug delivery systems (CDDS) of glycine, but acted rather as drugs on their own. Phthaloyl glycine was excreted unchanged in the urine while the urinary metabolites of the glycinamide derivatives were phthaloyl glycine and phthaloyl glycinamide. In this analogous series of phthalimide derivatives, minor chemical changes affected dramatically the compounds’ pharmacokinetics. The current study demonstrates the benefit of the SPPR approach in developing and selecting a potent antiepileptic compound in intact animals based not only on its intrinsic pharmacodynamic activity, but also on its better pharmacokinetic profile.
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REFERENCES
F. E. Dreifuss. New anticonvulsant drugs in “Epilepsy, Progress in Treatment,” M. Dam, S. I. Johannessen, B, Nilsson and M. Sillapaa (eds), Wiley & Sons, NY, 1987, pp. 247–256.
E. Roberts, T. N. Chase, D. B. Tower (eds.): “GABA in Nervous System Function,” Raven Press, NY (1976).
P. L. Morselli and R. Palminteri: Progabide. In. R. H. Levy, F. E. Dreifuss, R. H. Mattson, B. S. Meldrum and J. K. Penry (eds.). Antiepileptic Drugs, 3rd ed., Raven Press, New York, 1989, pp 887–905.
M. Bialer. Comparative pharmacokinetics of the newer antiepileptic drugs. Clin. Pharmacokinet. 24, 441–452 (1993).
S. M. Grant and R. C. Heel. Vigabatrin—a review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in epilepsy and disorders of motor control. Drugs. 41, 889–926 (1991).
D. Chadwick (ed). New Trends in Epilepsy Management: The Role of Gabapentin. Royal Society of Medicine Services Ltd., London, 1993.
J. Roba, R. Cavalier, A. Cordi, H. Gorissen, M. Herin, P. Janssens de Varebeke, C. Onkelinx, M. Remacle and W. van Dorsser. Milacemide in “New Anticonvulsant Drugs,” B. S. Meldrum and R. J. Porter (eds.), John Libby, London 1986, pp. 179–190.
J. Liu, N. Seiler, C. Marescaux, A. Depaulis and M. Vergns. Potentiation of γ-vinyl GABA (vigabatrin) effects by glycine. Eur. J. Pharmacol. 182, 109–115 (1990).
E. Toth and A. Lajtha. Glycine potentiates the action of some anticonvulsant drugs in some seizure models. Neurochem. Res. 8, 1711–1718 (1984).
J. D. Wood, P. Krogsgaard-Larsen and A. Schousboe. Amplification by glycine of the effect of the GABA transport inhibitor THPO on synaptosomal GABA level. Neurochem. Res. 13, 917–921 (1988).
N. Seiler and S. Sarhan. Synergistic anticonvulsant effects of a GABA agonist and glycine. Gen. Pharmacol. 15, 367–369 (1984).
P. Krogsgaard-Larsen, H. Hieds, E. Falach, F. S. Jorgensen and L. Neilsen. Recent advances in GABA agonists, antagonists and uptake inhibitors: Structure-activity relationships and therapeutic potential. Advanc. Drug Res. 17, 382–456 (1988).
E. Pop, M. E. Brewster and N. Bodor. Improved central nervous system delivery and activity of antiepileptic drugs. Drug Future 16, 221–248 (1991).
N. Bodor and M. E. Brewster. Problems of delivery of drugs to the brain. Pharmacol. Ther. 19, 337–386 (1993).
M. A. Rogawski and R. J. Porter. Antiepileptic Drugs: Pharmacological mechanism and clinical efficacy with consideration of promising developmental stage compounds. Pharmacol. Rev. 42, 223–286 (1990).
K. Nakagawa and R. I. Huxtable. The anticonvulsive action of two liphophilic taltrimide derivatives. Neurochem. Int. 7, 819–824 (1985).
D. Wiechert. The effects of succinyl-GABA derivatives on experimental seizures. In Epilepsy: A Clinical and Experimental Research. Mongr. Neural. Sci. Krager, Basel Vo,. 5, 1980, pp 160–162.
S. Bhowmick, M. Pal and S. P. Pal. Synthesis and anticonvulsant activity of N-phthaloyl GABA—a new GABA derivative. Ind. J. Exp. Biol. 27, 805–808 (1989).
M. Gibaldi and D. Perrier. Pharmacokinetics, 2nd edn., Marcel Dekker, New York, 1982.
K. Yamaoka. Methods for Pharmacokinetic Analysis for Personal Computers, edn 2, Nanko-D Ltd., Tokyo, 1986, p. 145.
R. J. Porter, J. J. Ceregino, G. D. Gladding, B. J. Hessie, H. J. Kupferberg, B. Scoville and B. G. White. Antiepileptic drug development program. Cliv. Clin. Q., 51, 293–305 (1984).
I. O. Edafiogho, K. R. Scott, J. A. Moore, V. A. Farrar and J. M. Nicholson. Synthesis and anticonvulsant activity of imidoxy derivatives. J. Med. Chem. 34, 387–392 (1991).
J. M. Chapman Jr., G. H. Cocolas and I. H. Hall. Hypolipidemic activity of phthalimide derivatives 1. N-substituted phthalimide derivatives. J. Med. Chem., 22, 1399–1408 (1979).
S. Banerji, S. Bhowmick, M. Bera, M. Pal and S. P. Pal. Antinociceptive action of GABA-mimetic agent-N-phthaloyl GABA. Ind. J. Exp. Biol. 29, 538–542 (1991).
S. Banerji, M. Habibuddin and S. P. Pal. Antiulcer and gastric secretory activity of N-phthaloyl-aminobutyric acid. Eur. J. Pharmacol. 219, 211–215 (1992).
M. Habibuddin, M. Pal and S. P. Pal. Neuropharmacology of amide derivatives of P-GABA. Ind. J. Exp. Biol. 30, 578–582 (1992).
Y. S. Andreichikov, V. V. Zalesov and N. A. Podushkina. Synthesis and biological activity of γ—(phthalimido) alkylcarbocylic acid amides. Khim. Farm. Zh. 14, 25–30 (1980).
G. Osuide, G. D. Lahan, J. A. Owoyale and I. O. Edafiogho. Preliminary studies on the anticonvulsant effects of methyl N-phthalimidoxy acetate (NMPA) in young chicks. Niger. J. Pharm. 12, 386–389 (1981).
Analgesic N-phthaloyl-amino acid amides. US 3,452, 141 (1969) Chem. Abst. 80982 u (1969).
M. Bianchi and F. Barzaghi. Compounds related structurally to-phthalimidoglutarimide (Thalidomide) I. Amides to aliphatic-phthalimido-acids. Frmaco. Ed. Sci. 20, 611–628 (1965).
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Salach, O.A., Hadad, S., Haj-Yehia, A. et al. Comparative Pharmacokinetic and Pharmacodynamic Analysis of Phthaloyl Glycine Derivatives with Potential Antiepileptic Activity. Pharm Res 11, 1429–1434 (1994). https://doi.org/10.1023/A:1018943906510
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DOI: https://doi.org/10.1023/A:1018943906510