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Chemistry and Pharmacology of GABAB Receptor Ligands

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Chemistry and Pharmacology of GABAB Receptor Ligands Provided for non-commercial research and educational use only. Not for reproduction, distribution or commercial use. This chapter was originally published in the book GABAB RECEPTOR PHARMACOLOGY: A TRIBUTE TO NORMAN BOWERY (Volume 58). The copy attached is provided by Elsevier for the author’s benefit and for the benefit of the author’s institution, for non-commercial research, and educational use. This includes without limitation use in instruction at your institution, distribution to specific colleagues, and providing a copy to your institution’s administrator. All other uses, reproduction and distribution, including without limitation commercial reprints, selling or licensing copies or access, or posting on open internet sites, your personal or institution’s website or repository, are prohibited. For exceptions, permission may be sought for such use through Elsevier's permissions site at: http://www.elsevier.com/locate/permissionusematerial From Wolfgang Froestl, Chemistry and Pharmacology of GABAB Receptor Ligands. In: Thomas P. Blackburn and S. J. Enna, editors, GABAB Receptor Pharmacology: A Tribute to Norman Bowery (Volume 58). Academic Press, 2010, p. 19. ISBN: 978-0-12-378647-0 © Copyright 2010, Elsevier Inc. Academic Press. Author's personal copy Wolfgang Froestl AC Immune SA, Lausanne, Switzerland Chemistry and Pharmacology of GABAB Receptor Ligands Abstract This chapter presents new clinical applications of the prototypic GABAB receptor agonist baclofen for the treatment of addiction by drugs of abuse, such as alcohol, cocaine, nicotine, morphine, and heroin, a novel baclofen prodrug Arbaclofen placarbil, the GABAB receptor agonist AZD3355 (Lesogabaran) currently in Phase 2 clinical trials for the treatment of gastro­ esophageal reflux disease, and four positive allosteric modulators of GABAB receptors (CGP7930, GS39783, NVP-BHF177, and BHFF), which have less propensity for the development of tolerance due to receptor desensitization than classical GABAB receptor agonists. All four compounds showed anxiolytic affects. In the presence of positive allosteric modulators the Advances in Pharmacology, Volume 58 1054-3589/10 $35.00 © 2010 Elsevier Inc. All rights reserved. 10.1016/S1054-3589(10)58002-5 Author's personal copy 20 Froestl “classical” GABAB receptor antagonists CGP35348 and 2-hydroxy-saclofen showed properties of partial GABAB receptor agonists. Seven micromolar affinity GABAB receptor antagonists, phaclofen; 2-hydroxy-saclofen; CGP’s 35348, 36742, 46381, 51176; and SCH50911, are discussed. CGP36742 (SGS742) showed statistically significant improvements of working memory and attention in a Phase 2 clinical trial in mild, but not in moderate Alzheimer patients. Eight nanomolar affinity GABAB receptor antagonists are presented (CGP’s 52432, 54626, 55845, 56433, 56999, 61334, 62349, and 63360) that were used by pharmacologists for numerous in vitro and in vivo investigations. CGP’s 36742, 51176, 55845, and 56433 showed antidepressant effects. Several compounds are also available as radioligands, such as [3H]CGP27492, [3H]CGP54626, [3H]CGP5699, and [3H] CGP62349. Three novel fluorescent and three GABAB receptor antagonists with very high specific radioactivity (>2,000 Ci/mmol) are presented. [125I] CGP64213 and the photoaffinity ligand [125I]CGP71872 allowed the iden­ tification of GABAB1a and GABAB1b receptors in the expression cloning work. I. Introduction Three years have passed since the author’s review “Chemistry of GABAB Modulators” appeared in the book The GABA Receptors, 3rd edition, edited by S. J. Enna and H. Möhler (Froestl et al., 2007). In this chapter I wish to outline new findings not covered in the 2007 paper and will add information which has not been covered in the 1997 and 2007 overviews (Froestl & Mickel, 1997). Norman G. Bowery discovered a novel GABA receptor in January 1980, when he found that GABA at a concentration of 4 mM decreased the release of [3H]-noradrenaline from rat atria and of [3H]-acetylcholine from preganglionic terminals in the rat superior cervical ganglion in vitro (Bowery et al., 1980). These effects could not be antagonized by the estab­ lished GABA antagonist bicuculline. Bowery showed that the GABA analo­ gue baclofen was as active as GABA in reducing evoked transmitter output and that the effect was stereoselective with the (R)-(À)-enantiomer being >100-fold more active than the (S)-(+)-enantiomer. The term GABAB recep­ tor was designated in March 1981 (Hill & Bowery, 1981; see also the review: Bowery, 1982). II. GABAB Receptor Agonists Baclofen, Ba-34647, was synthesized in September 1962 by Heinrich Keberle of Ciba, Basel, Switzerland, based on the idea to enhance the Author's personal copy Chemistry and Pharmacology of GABAB Receptor Ligands 21 Cl Cl O H H O O N H O OH H2N O O OH (R)-(–)-Baclofen Arbaclofen placarbil H O H N NH 2 OH HOOC 2 (R)-(–)-Phenibut Gabapentin FIGURE 1 Structures of (R)-(À)-baclofen, its prodrug, (R)-(À)-Phenibut, and Gabapentin. lipophilicity of GABA (calculated log P = À2.13; Cates, 1985) in order to achieve penetration of the blood–brain barrier (BBB; Keberle, Faigle, & Wilhelm, 1968). The lipophilicity of baclofen with a logD of À0.96 (Leisen et al., 2003) is still insufficient to bring the compound into the brain by passive diffusion. However, baclofen is transported into the brain by inter­ action with the large neutral amino acid transporter (Audus & Borchardt, 1986; van Bree et al., 1988, 1991). Conversely, the restricted distribution of baclofen in the brain interstitial fluid is due to an efficient efflux from the brain through the BBB regulated by a probenecid-sensitive organic anion transporter (Deguchi et al., 1995). In 1975 William Bencze resolved baclofen into the two enantiomers, (R)-(À)-baclofen (CGP11973A; Fig. 1)and( S)-(+)-baclofen (CGP11974A). Racemic and (R)-(À)-baclofen depressed the patellar, flexor, linguo­ mandibular, and the H-reflex in cats in a dose-dependent fashion (Olpe et al., 1978). Binding studies confirmed these findings: the IC50 values for (R)-(À)-baclofen, (S)-(+)-baclofen, and racemic baclofen for the inhibition of 3 binding of [ H]-baclofen to GABAB receptors of cat cerebellum are 15 nM, 1,770 nM, and 35 nM, respectively (Froestl et al., 1995a). The crystal struc­ ture of (R)-(À)-baclofen hydrochloride was published by Chang et al. (1982). A. Clinical Use of Baclofen Baclofen was marketed as Lioresal in 1972 and since then has been shown to exert beneficial clinical effects in many diverse indications: 1. As muscle relaxant in spasticity for patients with hemi- and tetraplegia (Brogden et al., 1974) including spasticity in multiple sclerosis (Brar et al., 1991; Giesser, 1985; Smith et al., 1991), after stroke (O’Brien Author's personal copy 22 Froestl et al., 1996), associated with Lewy body dementia (Moutoussis & Orrell, 1996), and in cerebral palsy in children (Buonaguro et al., 2005; Scheinberg et al., 2006) and adults (Krach, 2009). 2. A very important breakthrough was achieved by administration of baclofen directly into the CSF via an implanted mini-pump, that is, intrathecal baclofen. Penn and coworkers achieved spectacular improvements of patients, some of whom were bedridden for up to 19 years, who regained their ability to walk (Kroin, 1992; Penn & Kroin, 1984, 1985, 1987). Many eminent neurologists took up this new method of treatment immediately (Becker et al., 1997; Becker et al., 1995; Dralle et al., 1985; Gianino et al., 1998; Ochs, 1993; Ochs et al., 1989; Rawlins, 1998). Quantitative measurements by Leisen et al. (2003) showed that intrathecal administration of doses up to 600 mg resulted in local plasma levels of 5–20 ng/g. In comparison, oral racemic baclofen at the very high dose of 100 mg gave concentrations of <3 ng/g in CSF. An additional benefit was a major reduction in the unwanted side effects with high doses required for systemic administration. 3. A welcome side effect of baclofen treatment is the marked improvement of bladder function in patients with spinal cord lesions (Frost et al., 1989; Nanninga et al., 1989; Rapidi et al., 2007; Taylor & Bates, 1979). Baclofen significantly reduced the K+-evoked calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) in guinea pig urinary bladder (Santicioli et al., 1991). 4. Oral and intrathecal baclofen is also the treatment of choice in stiff- man syndrome (Silbert et al., 1995; Stayer et al., 1997; Whelan, 1980). A patient bedridden for 3 years was able to walk on the 13th day of treatment with 90 mg baclofen daily (Miller & Korsvik, 1981). 5. And in tetanus (Boots et al., 2000; Demaziére et al., 1991; Engrand & Benhamou, 2001; Engrand et al., 1999; Müller et al., 1987; Santos et al., 2004). 6. Baclofen is an efficient medication in several manifestations of pain, such as in trigeminal neuralgia. Pioneered by Fromm et al., baclofen either alone or in combination with carbamazepine or phenytoin achieved substantial pain relief (Baker et al., 1985; Fromm, 1994; Fromm et al., 1980, 1984). Interestingly, Fromm observed that (R)­ (À)-baclofen was 5 times more potent than racemic baclofen (Fromm & Terrence, 1987; Terrence et al., 1983). This may relate to papers by Sawynok and Dickson (1984, 1985) showing that (S)-(+)- = d-baclofen may act as an antagonist at baclofen receptors. This question has never been resolved. 7. Baclofen was effective in the treatment of cluster headache (Hering- Hanit & Gadoth, 2000, 2001) and in the prevention of migraine (Hering-Hanit, 1999). A very recent paper reveals functional Author's personal copy Chemistry and Pharmacology of GABAB Receptor Ligands 23 redundancy of GABAB receptors in peripheral nociceptors in vivo, which led to the conclusion that GABAB receptors in the peripheral nervous system play a less important role than those in the CNS in the regulation of pain (Gangadharan et al., 2009). Generally it is believed that baclofen exerts the analgesic properties by reduction of the release of L-glutamate, substance P, and calcitonin gene- related peptide (CGRP) from primary afferent terminals (Enna & McCarson, 2006; Kaupmann et al., 2001). 8. Baclofen is effective in reducing the craving for alcohol.
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