Pharm. Pharmacol. Commun. 1999, 5: 243±247 # 1999 Pharm. Pharmacol. Commun. Pharmacological Evaluation of New Baclofen Derivatives JEAN GUILLON, VE Â RONIQUE LEVASSEUR*, PASCAL SONNET, SILVIA STIEBING, MICHEL BOULOUARD*, PATRICK DALLEMAGNE, MARIE-ANNE QUERMONNE* AND SYLVAIN RAULT Centre d'Etudes et de Recherche sur le Me Âdicament de Normandie, Laboratoire de Pharmacochimie, and *Laboratoire de Pharmacologie, UFR des Sciences Pharmaceutiques, 1 rue Vaube Ânard, 14032 Caen Cedex, France Abstract The synthesis and in-vivo central pharmacological properties, in particular antinociceptive activity, of some new baclofen derivatives is described. The delayed antinociceptive activity of the N-tri¯uoroacetyl analogue of baclofen is also characterized. Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the vertebrate and invertebrate nervous system. It binds to three dif- ferent subtypes of receptors, namely, GABA A , GABA B and GABA C . With respect to the GABA B receptor, it appears to be involved in various phy- siological effects such as analgesia, cardiovascular effects and depression. Among the ligands of this receptor, baclofen (4-amino-3-(4-chlorophenyl) butyric acid) (Figure 1) is a selective agonist used clinically as an antispastic and myorelaxant (Ped- ersen et al 1974). Other GABA B agonists as baclofen analogues, such as CGP-27492 and CGP- 35024 (Bittiger et al 1988) have been described, while some phosphinic or sulphonic analogues, such as phaclofen or saclofen (Drew et al 1990) exhibit GABA B antagonist activity. Froest et al (1993) showed that weak pharmacomodulation of GABA can lead to compounds with either agonist or antagonist GABA B activity. The aim of this study was to describe the synth- esis of new mono or bicyclic derivatives of baclo- fen and to investigate their central pharmacological properties in mice. In particular, the compounds were tested for antinociceptive activity and com- pared with the pharmacological and structural reference baclofen. The GABA B modulation of this antinociceptive effect was also veri®ed for the more active derivatives by eventual attenuation of this action by CGP-35348, a selective GABA B antagonist (Olpe et al 1990). Materials and Methods Chemical procedures Melting points were determined on a Ko¯er block and are uncorrected. IR spectra were recorded on an Unicam Mattson 1000 spectrometer. 1 H, 13 C and 1 H-COSY NMR spectra were recorded on a Jeol JNM-LA 400 spectrometer (400 MHz) using CDCl 3 or d 6 -DMSO as solvent. Chemical shifts (d ppm) refer to tetramethylsilane which was used as an internal reference. NH, NH 2 and OH signals appeared as broad singlets exchangeable with D 2 O. Key: t  triplet, s  singlet, d  doublet, dd  double doublet, m  multiplet. Elemental analyses (C, H, N) were performed by INSA, Rouen, France and agreed with the proposed structures within  03% of the theoretical values. 3-(4-Chlorophenyl)-4-(2,2,2-tri¯uoroacetylamino)- butyric acid (5) To a suspension of 2 g (9 55 mmol) baclofen in 70 mL dry diethyl ether, 15 mL tri- ¯uoroacetylanhydride was added. The solution was stirred at room temperature for 30 min and then evaporated to dryness. The residue was stirred overnight in a saturated aqueous solution of sodium hydrogencarbonate, ®ltered to eliminate the 4-(4- chlorophenyl) pyrrolidin-2-one 6 and acidi®ed to pH 1. The precipitate was ®ltered, washed with water and dried. White crystals (38%); mp 122  C; IR (KBr) n: 3440±2570 (OH), 3335 (NH), 1700 cm 1 (CO); 1 H NMR (CDCl 3 ) d:267 (1H, dd, J  1640 and 680, H-2b), 274 (1H, dd, J  1640 and 710, H-2a), 339 (1H, m, H-3), 348 (1H, m, H-4b), 370 (1H, m, H-4a), 650 (1H, t, J  560, NH), 714 (2H, d, J  860, H-3 0 and H- 5 0 ), 732 (2H, d, J  860, H-2 0 and H-6 0 ); 13 C NMR (CDCl 3 ) d: 378(CH), 403(CH 2 ), 445 Correspondence: S. Rault, Centre d'Etudes et de Recherche sur le Me Âdicament de Normandie, Laboratoire de Pharmaco- chimie, UFR des Sciences Pharmaceutiques, 1 rue Vaube Ânard, 14032 Caen Cedex, France.