Abstract
Although benzodiazepines (BZDs) offer a wide spectrum of antiepileptic activity against diverse types of epileptic seizures, their use in the treatment of epilepsy is limited because of adverse effects, loss of efficacy (tolerance), and development of physical and psychological dependence. BZDs act as positive allosteric modulators of the inhibitory neurotransmitter GABA by binding to the BZD recognition site (“BZD receptor”) of the GABAA receptor. Traditional BZDs such as diazepam or clonazepam act as full agonists at this site, so that one strategy to resolve the disadvantages of these compounds would be the development of partial agonists with lower intrinsic efficacy at the BZD site of the GABAA receptor. Several BZD site partial or subtype selective compounds, including bretazenil, abecarnil, or alpidem, have been developed as anxioselective anxiolytic drugs, but epilepsy was not a target indication for such compounds. More recently, the imidazolone derivatives imepitoin (ELB138) and ELB139 were shown to act as low-affinity partial agonists at the BZD site of the GABAA receptor, and imepitoin was developed for the treatment of epilepsy. Imepitoin displayed a broad spectrum of anticonvulsant activity in diverse seizure and epilepsy models at tolerable doses, and, as expected from its mechanism of action, lacked tolerance and abuse liability in rodent and primate models. The more favorable pharmacokinetic profile of imepitoin in dogs versus humans led to the decision to develop imepitoin for the treatment of canine epilepsy. Based on randomized controlled trials that demonstrated antiepileptic efficacy and high tolerability and safety in epileptic dogs, the drug was recently approved for this indication in Europe. Hopefully, the favorable profile of imepitoin for the treatment of epilepsy in dogs will reactivate the interest in partial BZD site agonists as new treatments for human epilepsy.
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References
Chang BS, Lowenstein DH. Epilepsy. N Engl J Med. 2003;349:1257–66.
Chandler K. Canine epilepsy: what can we learn from human seizure disorders? Vet J. 2006;172:207–17.
Löscher W, Schmidt D. Modern antiepileptic drug development has failed to deliver: ways out of the current dilemma. Epilepsia. 2011;52:657–78.
Löscher W, Schmidt D. Experimental and clinical evidence for loss of effect (tolerance) during prolonged treatment with antiepileptic drugs. Epilepsia. 2006;47:1253–84.
Rogawski MA, Löscher W. The neurobiology of antiepileptic drugs. Nat Rev Neurosci. 2004;5:553–64.
Vinkers CH, Olivier B. Mechanisms underlying tolerance after long-term benzodiazepine use: a future for subtype-selective GABA(A) receptor modulators? Adv Pharmacol Sci. 2012;2012:416864.
Haefely W. Partial agonists of the benzodiazepine receptor: from animal data to results in patients. Adv Biochem Psychopharmacol. 1988;45:275–92.
Stephens DN, Sarter M. Bidirectional nature of benzodiazepine receptor ligands extends to effects on vigilance. Psychopharmacol Ser. 1988;6:205–17.
Haefely W, Martin JR, Schoch P. Novel anxiolytics that act as partial agonists at benzodiazepine receptors. Trends Pharmacol Sci. 1990;11:452–6.
Haefely W, Facklam M, Schoch P, et al. Partial agonists of benzodiazepine receptors for the treatment of epilepsy, sleep, and anxiety disorders. Adv Biochem Psychopharmacol. 1992;47:379–94.
Costa E, Guidotti A. Benzodiazepines on trial: a research strategy for their rehabilitation. Trends Pharmacol Sci. 1996;17:192–200.
Stephens DN, Turski L, Jones GH, et al. Abecarnil: a novel anxiolytic with mixed full agonist/partial agonist properties in animal models of anxiety and sedation. In: Stephens DN, editor. Anxiolytic β-carbolines. Berlin: Springer; 1993. p. 79–95.
Skolnick P. Anxioselective anxiolytics: on a quest for the Holy Grail. Trends Pharmacol Sci. 2012;33:611–20.
Löscher W, Hönack D, Scherkl R, et al. Pharmacokinetics, anticonvulsant efficacy and adverse effects of the β-carboline abecarnil, a novel ligand for benzodiazepine receptors, after acute and chronic administration in dogs. J Pharmacol Exp Ther. 1990;255:541–8.
Löscher W. Abecarnil shows reduced tolerance development and dependence potential in comparison to diazepam: animal studies. In: Stephens DN, editor. Anxiolytic β-carbolines: from molecular biology to the clinic. Berlin: Springer; 1993. p. 96–112.
Turski L, Stephens DN, Jensen LH, et al. Anticonvulsant action of the β-carboline abecarnil: studies in rodents and baboon, Papio papio. J Pharmacol Exp Ther. 1990;253:344–52.
Sannerud CA, Ator NA, Griffiths RR. Behavioral pharmacology of abecarnil in baboons: self-injection, drug discrimination and physical dependence. Behav Pharmacol. 1992;3:507–16.
Rostock A, Tober C, Dost R, et al. AWD-131–138. Drugs Future. 1998;23:253–5.
Sigel E, Baur R, Netzer R, et al. The antiepileptic drug AWD 131–138 stimulates different recombinant isoforms of the rat GABA(A) receptor through the benzodiazepine binding site. Neurosci Lett. 1998;245:85–8.
Grunwald C, Rundfeldt C, Lankau HJ, et al. Synthesis, pharmacology, and structure-activity relationships of novel imidazolones and pyrrolones as modulators of GABAA receptors. J Med Chem. 2006;49:1855–66.
Gasparic A. Investigations on biotransformation of AWD 131–138. Doctoral thesis. Faculty of Bioscience, Pharmacy and Psychology, University of Leipzig, Leipzig, Germany; 2005.
Löscher W, Potschka H, Rieck S, et al. Anticonvulsant efficacy of the low-affinity partial benzodiazepine receptor agonist ELB 138 in a dog seizure model and in epileptic dogs with spontaneously recurrent seizures. Epilepsia. 2004;45:1228–39.
Frey H-H, Löscher W. Pharmacokinetics of anti-epileptic drugs in the dog: a review. J Vet Pharmacol Ther. 1985;8:219–33.
Potschka H, Fischer A, von Rüden EL, et al. Canine epilepsy as a translational model? Epilepsia. 2013;54:571–9.
European Medicines Agency (EMA). Summary of product characteristics (SPC) for Pexion (imepitoin). 2013. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/veterinary/medicines/002543/vet_med_000268.jsp&mid=WC0b01ac058008d7a8.
Langen B, Egerland U, Bernoster K, et al. Characterization in rats of the anxiolytic potential of ELB139 [1-(4-chlorophenyl)-4-piperidin-1-yl-1,5-dihydro-imidazol-2-on], a new agonist at the benzodiazepine binding site of the GABAA receptor. J Pharmacol Exp Ther. 2005;314:717–24.
Kupferberg HJ. Antiepileptic drug development program: a cooperative effort of government and industry. Epilepsia. 1989;30(Suppl 1):S51–6.
Rostock A, Tober C, Rundfeldt C, et al. D-23129: a new anticonvulsant with a broad spectrum activity in animal models of epileptic seizures. Epilepsy Res. 1996;23:211–23.
Rundfeldt C. The new anticonvulsant retigabine (D-23129) acts as an opener of K+ channels in neuronal cells. Eur J Pharmacol. 1997;336:243–9.
Rundfeldt C, Netzer R. The novel anticonvulsant retigabine activates M-currents in Chinese hamster ovary-cells transfected with human KCNQ2/3 subunits. Neurosci Lett. 2000;282:73–6.
Rogawski MA. KCNQ2/KCNQ3 K+ channels and the molecular pathogenesis of epilepsy: implications for therapy. Trends Neurosci. 2000;23:393–8.
Lankau HJ, Unverferth K, Grunwald C, et al. New GABA-modulating 1,2,4-oxadiazole derivatives and their anticonvulsant activity. Eur J Med Chem. 2007;42:873–9.
Unverferth K, Dorre R, Korner B, et al. Synthesis and anticonvulsant activity of 3-carbamoyl-4-aryl-isoquinolin-1(2H)-ones. Arch Pharm (Weinheim). 1991;324:809–14.
Unverferth K, Engel J, Hofgen N, et al. Synthesis, anticonvulsant activity, and structure-activity relationships of sodium channel blocking 3-aminopyrroles. J Med Chem. 1998;41:63–73.
Lankau HJ, Menzer M, Rostock A, et al. 3-Amino- and 5-aminopyrazoles with anticonvulsant activity. Arch Pharm (Weinheim). 1999;332:219–21.
Lankau HJ, Menzer M, Rostock A, et al. Synthesis and anticonvulsant activity of new 4-aminopyrazoles and 5-aminopyrazol-3-ones. Pharmazie. 1999;54:705–6.
Rostock A, Tober C, Rundfeldt C, et al. AWD 140–190: a new anticonvulsant with a very good margin of safety. Epilepsy Res. 1997;28:17–28.
Langen B, Rundfeldt C, Dost R, et al., Inventors. Method of treating or preventing central nervous system disorders with compounds having selectivity for the alpha 3 subunit of the benzodiazepine receptor. Patent application WO 2005/004867 A2; published 2005.
Heinecke K, Thiel W. Identity and physicochemical properties of 1-(4-chlorophenyl)-4-morpholino-imidazolin-2-one, AWD 131–138. Pharmazie. 2001;56:458–61.
Rostock A, Tober C, Dost R, et al. AWD 131–138: anxiolytic and anticonvulsant activities without side effects in animals. Behav Pharmacol. 1998;9(Suppl 1):S79.
Tober C, Rostock A, Bartsch R. Anticonvulsant profile of AWD 131–138, a derivative of a series of imidazolinones. Naunyn-Schmiedeberg’s Arch Pharmacol. 1998;357(Suppl 4):R98.
Tober C, Rostock A, Bartsch R. AWD 131–138: a derivative of a series of imidazolinones with anticonvulsant activity. Naunyn-Schmiedeberg’s Arch Pharmacol. 1998; 358 Suppl 1:P35.
Tober C, Rostock A, White HS, et al. Anticonvulsant activity of AWD 131–138 in genetic animal models of epilepsy. Naunyn-Schmiedeberg’s Arch Pharmacol. 1999; 359 Suppl:R97.
McNamara JO, Byrne MC, Dasheiff RM, et al. The kindling model of epilepsy: a review. Prog Neurobiol. 1980;15:139–59.
Dost R, Langen B, Rundfeldt C. The α-3 subunit selective benzodiazepine agonist ELB139 does not induce tolerance in animal models for anxiety and epilepsy. Soc Neurosci Abstr. 2005;678.1.
Tober C, Stark B, Bartsch R, et al. Effects of AWD 131–138 in the amygdala kindling model of focal epilepsy. Naunyn-Schmied Arch Pharmacol. 2000;361 Suppl:R98.
File SE, Lister RG. Do the reductions in social interaction produced by picrotoxin and pentylenetetrazole indicate anxiogenic actions? Neuropharmacology. 1984;23:793–6.
Rabe H, Kronbach C, Rundfeldt C, et al. The novel anxiolytic ELB139 displays selectivity to recombinant GABA(A) receptors different from diazepam. Neuropharmacology. 2007;52:796–801.
Langen B, Dost R, Rundfeldt C. Antipsychotic effect of the alpha-3 subunit selective benzodiazepine agonist ELB139 in rats. Pharmacopsychiatry. 2005;38:A135.
Yasar S, Bergman J, Munzar P, et al. Evaluation of the novel antiepileptic drug, AWD 131–138, for benzodiazepine-like discriminative stimulus and reinforcing effects in squirrel monkeys. Eur J Pharmacol. 2003;465:257–65.
Rieck S, Rundfeldt C, Tipold A. Anticonvulsant activity and tolerance of ELB138 in dogs with epilepsy: a clinical pilot study. Vet J. 2006;172:86–95.
Frey H-H, Göbel W, Löscher W. Pharmacokinetics of primidone and its active metabolites in the dog. Arch Int Pharmacodyn Ther. 1979;242:14–30.
Gasparic A, Schupke H, Olbrich M, et al. Morpholine ring oxidation of AWD 131–138, a novel anxiolytic and anticonvulsant, is catalysed by CYP1A1/2. Drug Metab Rev. 2001;33(Suppl. 1):89.
Whyatt RM, Garte SJ, Cosma G, et al. CYP1A1 messenger RNA levels in placental tissue as a biomarker of environmental exposure. Cancer Epidemiol Biomark Prev. 1995;4:147–53.
Rundfeldt C, Dost R, Löscher W, et al., Inventors. Use of dihydroimidazolones for the treatment of epilepsy in dogs. Patent application WO 2004/032938 A1; published 2004; granted European patent EP1553952B1. 2008.
Rundfeldt C, Schlichthaar R, Grunwald M, et al. The α-3 subunit selective benzodiazepine ligand ELB139 is well tolerated without sedation in healthy male volunteers while exerting pharmacodynamic effects assessed as power spectrum changes in Fourier-transformed EEG. Soc Neurosci Abstr. 2005;678.15.
European Medicines Agency (EMA). European Public Assessment Report (EPAR) for Pexion (imepitoin). 2012. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/veterinary/002543/WC500140842.pdf.
Shihab N, Bowen J, Volk HA. Behavioral changes in dogs associated with the development of idiopathic epilepsy. Epilepsy Behav. 2011;21:160–7.
Löscher W, Schwartz-Porsche D, Frey H-H, et al. Evaluation of epileptic dogs as an animal model of human epilepsy. Arzneim-Forsch (Drug Res). 1985;35:82–7.
Leppik IE, Patterson EN, Coles LD, et al. Canine status epilepticus: a translational platform for human therapeutic trials. Epilepsia. 2011;52(Suppl 8):31–4.
Steinmetz S, Tipold A, Löscher W. Epilepsy after head injury in dogs: a natural model of posttraumatic epilepsy. Epilepsia. 2013;54:580–8.
Kanner AM. The treatment of depressive disorders in epilepsy: what all neurologists should know. Epilepsia. 2013;54(Suppl 1):3–12.
Löscher W, Rogawski MA. How theories evolved concerning the mechanism of action of barbiturates. Epilepsia. 2012;53(Suppl 8):12–25.
Löscher W, Hoffmann K, Twele F, et al. The novel antiepileptic drug imepitoin compares favourably to other GABA-mimetic drugs in a seizure threshold model in mice and dogs. Pharmacol Res. 2013;77:39–46.
Rostock A, Tober C, Dost R, et al. AWD 131–138 is a potential novel anxiolytic without sedation and amnesia: a comparison with diazepam and buspirone. Naunyn-Schmied Arch Pharmacol. 1998;358(Suppl 1):R68.
Acknowledgments
We thank Dr. Klaus Unverferth and Dr. Hans-Joachim Lankau (both previously AWD) for their kind support in describing the chemical synthesis, Dr. Antje Gasparic (previously AWD) for her support in retrieving data from her doctoral thesis, Dr. Michael A. Rogawski for providing Fig. 1, and Dr. Richard W. Olsen for advice relating to Fig. 1. The authors of this article confirm that they have full control of all primary data and certify that no funding has been received for the preparation of this manuscript. C. Rundfeldt was a former employee of AWD and Elbion (which developed imepitoin) and acted as a consultant for Boehringer Ingelheim. W. Löscher acted as a consultant for AWD, Elbion, and Boehringer Ingelheim during the development of imepitoin. The authors have no patent rights to the compounds described in this review.
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Rundfeldt, C., Löscher, W. The Pharmacology of Imepitoin: The First Partial Benzodiazepine Receptor Agonist Developed for the Treatment of Epilepsy. CNS Drugs 28, 29–43 (2014). https://doi.org/10.1007/s40263-013-0129-z
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DOI: https://doi.org/10.1007/s40263-013-0129-z