(R)-baclofen

(R)-Baclofen is a selective GABAB receptor agonist. GABAB receptors are metabotropic receptors which produce slow inhibitory signals.

[Double blind placebo controlled randomized pilot clinical trial of baclofen (Baclosan(R)) for alcohol dependence].[Pubmed:26356398]

Zh Nevrol Psikhiatr Im S S Korsakova. 2015;115(6):53-62.

AIM: To study efficacy and safety of baclofen for treatment of alcohol dependence. MATERIAL AND METHODS: 32 patients with alcohol dependence had been randomized into one of two treatment groups (16 patients in each): patients of the 1st group were treated with baclofen (50 mg/day) for 3 months while patients of the 2nd one received identically looking placebo. All the study subjects were scheduled to come to the clinic on the weekly basis to control alcohol use and compliance with the study medications (by riboflavin marker in urine) and also - for psychiatric evaluations (severity of craving for alcohol, anxiety and depression). Alcohol use evaluated with the Time Line Follow Back technique and gamma-glutamiltranspeptidase activity in blood. To assess anxiety Spielberger state-trait inventory and Hamilton scale were used. Depression was assessed with Montgomery-Ashberg scale. To evaluate carving for alcohol used Obsessive-Compulsive Drinking scale, Penn Alcohol Craving scale, and Visual Analog Scale of Craving. Overall treatment effect assessed with the Clinical Global Impression scale. The study design was double blind. RESULTS AND CONCLUSION: Baclofen did no differ significantly from placebo on either of primary or secondary outcome variables. However, primary outcome variables of retention in treatment and drinking were slightly better in the baclofen group compared to placebo, and those differences were close to the level of statistical significance. There were no differences between the groups in either rate of adverse events or liver enzymes activity which is an evidence of safety and good tolerability of baclofen in alcohol dependent patients. Further studies of baclofen for alcohol dependence in the larger sample size are needed.

Efficient Synthesis of beta-Aryl-gamma-lactams and Their Resolution with (S)-Naproxen: Preparation of (R)- and (S)-Baclofen.[Pubmed:26690390]

Molecules. 2015 Dec 10;20(12):22028-43.

An efficient synthesis of enantiomerically-pure beta-aryl-gamma-lactams is described. The principal feature of this synthesis is the practical resolution of beta-aryl-gamma-lactams with (S)-Naproxen. The procedure is based on the Michael addition of nitromethane to benzylidenemalonates, which was easily obtained, followed by the reduction of the gamma-nitroester in the presence of Raney nickel and the subsequent saponification/decarboxylation reaction. The utility of this methodology was highlighted by the preparation of enantiomerically-pure (R)- and (S)-Baclofen hydrochloride.

Differential effects of R-isovaline and the GABAB agonist, baclofen, in the guinea pig ileum.[Pubmed:27521870]

Eur J Pharmacol. 2016 Nov 15;791:85-90.

R-isovaline is a non-proteinogenic amino acid which produces analgesia in a range of nociceptive assays. Mediation of this effect by metabotropic receptors for gamma-aminobutyric acid (GABA) and glutamate, demonstrated by previous work, may depend on the type of tissue or receptor system. The objective of this study was to assess the activity of R-isovaline acting at GABAB and group II metabotropic glutamate receptors in guinea pig ileum, which is known to exhibit well-defined responses to GABAB agonists such as baclofen. The effects of bath-applied R-isovaline and RS-baclofen were examined on electrically evoked contractions of guinea pig ileum and during GABAB antagonism by CGP52432. In separate experiments, the group II metabotropic glutamate receptor agonist, LY354740 was applied to determine the functional presence of these receptors. R-isovaline (1-100mM) decreased the amplitude of ileal muscle contractions and increased tension. RS-baclofen reduced contraction amplitude, but decreased tension. CGP52432 did not prevent the effects of R-isovaline on contraction amplitude, but antagonized effects of RS-baclofen on contraction amplitude. The group II metabotropic glutamate receptor agonist, LY354740, produced no detectable effects on evoked contractions. R-isovaline differed significantly from RS-baclofen in its actions in the guinea pig ileum, indicated in particular by the finding that CGP52432 blocked only the effects of RS-baclofen. The ileal tissue did not respond to a group II metabotropic glutamate receptor agonist, previously shown to co-mediate R-isovaline analgesia. These findings raise the possibility of a novel therapeutic target at unknown receptors for R-isovaline-like compounds in the guinea pig ileum.

R(+)-Baclofen, but Not S(-)-Baclofen, Alters Alcohol Self-Administration in Alcohol-Preferring Rats.[Pubmed:27148096]

Front Psychiatry. 2016 Apr 18;7:68.

Racemic baclofen [(+/-)-baclofen] has repeatedly been reported to suppress several -alcohol-motivated behaviors, including alcohol drinking and alcohol -self-administration, in rats and mice. Recent data suggested that baclofen may have bidirectional, stereospecific effects, with the more active enantiomer, R(+)-baclofen, suppressing alcohol intake and the less active enantiomer, S(-)-baclofen, stimulating alcohol intake in mice. The present study was designed to investigate whether this enantioselectivity of baclofen effects may also extend to the reinforcing properties of alcohol in rats. To this end, selectively bred Sardinian alcohol-preferring (sP) rats were initially trained to lever respond on a fixed ratio 4 (FR4) schedule of reinforcement for alcohol (15%, v/v) in daily 30-min sessions. Once responding had stabilized, rats were tested with vehicle, (+/-)-baclofen (3 mg/kg), R(+)-baclofen (0.75, 1.5, and 3 mg/kg), and S(-)-baclofen (6, 12, and 24 mg/kg) under the FR4 schedule of reinforcement. Treatment with 3 mg/kg (+/-)-baclofen reduced the number of lever responses for alcohol and estimated amount of self-administered alcohol by approximately 60% in comparison to vehicle treatment. R(+)-baclofen was approximately twice as active as (+/-)-baclofen: treatment with 1.5 mg/kg R(+)-baclofen decreased both variables to an extent similar to that of the decreasing effect of 3 mg/kg (+/-)-baclofen. Conversely, treatment with all doses of S(-)-baclofen failed to affect alcohol self administration. These results (a) confirm that non-sedative doses of (+/-)-baclofen effectively suppressed the reinforcing properties of alcohol in sP rats and (b) apparently do not extend to operant alcohol self-administration in sP rats the capability of S(-)-baclofen to stimulate alcohol drinking in mice.

Effects of phaclofen and the enantiomers of baclofen on cardiovascular responses to intrathecal administration of L- and D-baclofen in the rat.[Pubmed:1654254]

Eur J Pharmacol. 1991 Apr 24;196(3):267-75.

In a previous study it was found that i.t. administration of L-baclofen decreased arterial pressure and heart rate while D-baclofen differentially increased arterial pressure. The objective of the present study was to determine which of these effects was blocked by prior administration of the GABAB receptor antagonist, phaclofen, and whether the effect of one enantiomer of baclofen could be blocked by prior administration of the other. The decreases in systolic and diastolic arterial pressures and in heart rate produced by i.t. administration of 70 nmol of L-baclofen were unaffected by i.t. administration of 7, 70 or 700 nmol of D-baclofen 10 min prior to administration of L-baclofen, but were blocked by administration of 5 mumol of phaclofen given 3-5 min prior to L-baclofen. On the other hand, the increases in systolic and diastolic arterial pressures induced by i.t. administration of 700 nmol of D-baclofen were blocked by 70 nmol but not by 7 nmol of L-baclofen, as well as by 2.5 mumol of phaclofen; the effect of L-baclofen cannot be attributed to a desensitization of D-baclofen-sensitive receptors as two successive doses of D-baclofen given 7 min apart had quantitatively similar effects. Phaclofen alone increased systolic and diastolic arterial pressures and heart rate. The results are interpreted as indicating that D-baclofen is not an antagonist of L-baclofen in this paradigm; rather, they suggest that L-baclofen reduces the effects of D-baclofen.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative stereostructure-activity studies on GABAA and GABAB receptor sites and GABA uptake using rat brain membrane preparations.[Pubmed:3016189]

J Neurochem. 1986 Sep;47(3):898-903.

The affinities of a number of analogues of gamma-aminobutyric acid (GABA) for GABAA and GABAB receptor sites and GABA uptake were studied using rat brain membrane preparations. Studies on the (S)-(+)- and (R)-(-)-isomers of baclofen, 3-hydroxy-4-aminobutyric acid (3-OH-GABA), and 4,5-dihydromuscimol (DHM) revealed different stereoselectivities of these synaptic mechanisms in vitro. Although (S)-3-OH-GABA and, in particular, (S)-DHM were more potent than the corresponding (R)-isomers as inhibitors of GABAA binding, the opposite stereoselectivity was demonstrated for the GABAB binding sites. Thus, (R)-3-OH-GABA and (R)-baclofen were more potent than the (S)-isomers as inhibitors of GABAB binding, (R)-baclofen being some five times more potent than (R)-3-OH-GABA. These two (R)-isomers actually have opposite orientation of the substituents on the GABA backbones, suggesting that the lipophilic substituent of (R)-baclofen interacts with a structural element of the GABAB receptor site different from that that binds the very polar hydroxy group of (R)-3-OH-GABA. The O-methylated analogue of 3-OH-GABA, 3-methoxy-4-aminobutyric acid (3-OCH3-GABA), did not interact significantly with GABAB sites. The homologues of GABA, trans-4-aminocrotonic acid (trans-ACA), muscimol, and 3-OH-GABA, that is, 5-aminovaleric acid (DAVA), trans-5-aminopent-2-enoic acid, homomuscimol, and 3-hydroxy-5-aminovaleric acid (3-OH-DAVA), respectively, were generally much weaker than the parent compounds, whereas 2-hydroxy-5-aminovaleric acid (2-OH-DAVA) showed a significantly higher affinity for GABAB sites than the corresponding GABA analogue.(ABSTRACT TRUNCATED AT 250 WORDS)