Chapter 1 Synthesis of (±)-Baclofen and Analogs (Homobaclofen, PCPGABA, Phaclofen, Saclofen)
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Chapter 1 Synthesis of (±)-Baclofen and analogs (Homobaclofen, PCPGABA, Phaclofen, Saclofen). 13 Chapter 1: Synthesis of (±)-Baclofen and analogs Section-I: Synthesis of (±)-Baclofen Section-II: Synthesis of (±)-Homobaclofen Section-III: Synthesis of (±)-PCPGABA Section-IV: Synthesis of (±)-Phaclofen and (±)-Saclofen 14 Section-I: Synthesis of (±)-Baclofen 1.0.1 Introduction 1.0.2 GABA The brain and the spinal cord are two main components of the central nervous system. The central nervous system (CNS) integrates information received from different body parts, coordinates and influences the activity of all parts of the body. The nervous system is made up of individual nerve cells called neurons through which nerve signals are transmitted as an electrical impulse. When a nerve impulse reaches to the end of the neuron it can jump over to the next cell using chemical messengers called neurotransmitters. Glutamate and GABA (Figure-1) are the most abundant neurotransmitters in the central nervous system, and especially in the cerebral cortex, where thinking occurs and sensations are interpreted. Glutamate acts as an excitatory neurotransmitter while GABA does the opposite. Figure-1 In 1950, Eugene Roberts and Jorge Awapara independently discovered that very large amounts of GABA was present in the mammalian central nervous system, 1 mg per gram, while undetectable in other tissues. Ernst Florey in 1953 showed that GABA was the unknown compound which inhibited the crayfish stretch receptor when applied exogenously.1 γ-Amino butyric acid 1 (GABA) is the major inhibitory neurotransmitter in the mammalian central nervous system (CNS) and synthesized by decarboxylation of glutamate using the enzyme glutamic acid decarboxylase (GAD). This enzyme converts L-glutamate to GABA and CO2, using pyridoxal phosphate as a cofactor (Figure-2). Figure-2 GABAs can be grouped into two broad classes: First class consists of ligand-gated ion channels or (GABAA and GABAC) (Table-1) while second class consists of G-protein- 15 2 coupled or GABAB receptors (Table-2) based on electrophysiological and binding studies.3 Table-1: Ligand-gated ion channel receptors Function type Ligand Ion channel Glutamate (non-NMDA class receptors) Na+/ K+ Excitatory Glutamate (NMDA class receptors) Na+/ K+ and Ca2+ Acetylcholine (nicotinic receptor) Na+/ K+ Serotonin (5HT3 class receptors) Na+/ K+ Inhibitory GABAA/ C and glycine receptors Cl¯ Table-2: Some Neurotransmitter G-protein-coupled receptors Glutamate receptors (metabotropic receptors) GABAB receptors Acetylcholine (muscarinic receptors) Dopamine receptors Epinephrine, norepinephrine Histamine receptors Serotonin (5HT1, 5HT2, 5HT4 receptors 1.0.2.1 Ligand-gated ion channel receptors 4,5 6 Muscimol 2, ibotenic acid 3, thiomuscimol 4, dihydromuscimol 5, isoguvacine 6 and isonipecotic acid 7 are the GABAA agonist and used to design the different classes of GABA analogues7 (Figure-3). Figure-3: GABAA agonists. 8 9 Bicuculline 8 and its quaternized analogue bicuculline methyl chloride (BMC) 9 are GABAA antagonists and have played a key role in studies on GABAA receptors. 10 Iso-THAZ 10, is a moderately potent GABAA antagonist. Gabazine 11, and its 11 derivatives 12, 13 showed very potent and selective GABAA antagonist effects. Pentylenetetrazole 14, and Picrotoxinin 15 (Figure-4) are non competitive GABAA antagonist.12 16 Figure-4: GABAA antagonists. 4,5,6,7-Tetrahydroisoxazolo[5,4]-3-pyridinol (THIP)13 16, Imidazole-4-acetic acid14 (IAA) 17 and Piperidine-4-sulphonic acid15 (PAS) 18 shows the characteristics of 16 partial GABAA agonists. The non fused THIP analogue 5-(4-piperidyl)-3-isoxazolol (4-PIOL) 19 was about 200 times less potent as an agonist than isoguvacine 6 and its response was competitively antagonized by bicuculline methyl chloride 9. The 3- isothiazolol analogue of 19, Thio-4-PIOL 20, was approximately equally active with 19 at GABAA binding sites, whereas the unsaturated analogue of 20, DH-Thio-4-PIOL 21, was significantly more efficacious.17 Compounds 22 and 23 also showed a potent 18 GABAA antagonist activity (Figure-5). 17 Figure-5: Partial GABAA agonists. Benzodiazepines (BDZs), barbiturates and steroids etc. (Figure-6) possesses a large number of binding sites for drugs and primary mechanism involves allosteric modulation of the GABAA receptor complex. Some examples are shown in Figure-6. Figure-6: Benzodiaxepines GABAC receptors are non-GABAA, non-GABAB (NANB) ionotropic GABA 19 receptors and they are bicuculline and baclofen-insensitive receptors. GABAC receptors share several agonists with GABAA receptors but the sensitivity of GABAC 20 receptors to GABA is much higher than that of GABAA receptors. The conformationally restricted GABA analogues, namely cis-4-amino-crotonic acid (CACA) 28 (fig.-7) and cis-2-aminomethyl-cyclopropane-carboxylic acid (CAMP) 29 (fig.-7) are GABA-like neuronal depressants which are not sensitive to 9 and they bind to a class of GABA receptor sites which do not recognize isoguvacine 6 or (R)- Baclofen.21 IAA 17 has recently been shown to be an antagonist at the retinal GABA 22 receptors, probably of the GABAC type. Also, 1,2,5,6-tetrahydro-4-pyridinylmethyl- phosphinic acid (TPMPA) 30 (fig.-7), a methyl-phosphonic acid derivative of 6, is a weak antagonist at GABAA receptors and a weak agonist at GABAB receptors, but 23 shows a highly potent antagonist effect at GABAC receptors. 18 Figure-7 1.0.2.2 G-Protein-Coupled Receptors/GABAB Receptors G-protein-coupled receptors are cell-surface receptors containing seven transmembrane α-helical regions with N-terminal segment on the exoplamic face and their C-terminal segment on the cytosolic face of the plasma membrane. Ligand binding to these receptors activates their associated trimeric signal transducing G protein, which in turn activates or inhibits an effectors enzyme that generates an intracellular specific second messenger or modulates an ion channel, causing a change in membrane potential.24 This large receptor super family has been divided based on their homology into three families: family A (rhodopsin receptor-like), family B (secretin receptor-like) and family C (metabotropic glutamate receptor-like, calcium sensing receptor, GABAB receptors and several pheromone receptors).25 GABAB receptors (GABABR) are metabotropic transmembrane receptors for gamma-amino butyric acid (GABA) that are linked via G-proteins to potassium 26 channels. The GABAB receptor is a G-protein coupled receptor (GPCR) that associates with a subset of G-proteins, that in turn regulate specific ion channels and trigger cAMP cascades. GABAB agonists inhibit basal and forskolin-stimulated neuronal adenylate cyclase in brain slices through a G protein-dependant mechanism that results in a 27 reduced level of intracellular cAMP. In addition, activation of GABAB receptors decreases Ca2+ conductance and increases K+ conductance in neuronal membranes.28 The importance of GABA in the central and peripheral nervous systems prompted the researchers to design an analogue which unlike GABA itself could readily access to the brain. 4-Amino-3-phenyl-butanoic acid 31 inhibits spinal reflexes after oral administration. Baclofen 32 emerged as a possible GABA-mimetic which could administered orally and activate GABAB receptors in a stereoselective manner. Many analogs of Baclofen are synthesized and tested for pharmacological properties. 4-amino-3-benzo[b]-2-furanyl- butanoic acid 33 and 4-amino3-(5-methoxy-benzo[b]-2-furanyl)-butanoic acid 34 29 showed affinity for the GABAB receptors. 4-amino-3-(7-methyl-benzo[b]-2-furanyl)- butanoic acid 35, 4-amino-3-(5-methyl2-thienyl)-butanoic acid 36, 4-amino-3-(5- 19 chloro-2-thienyl)-butanoic acid 37, and 4-amino-3-(2′,4′-dichloro-phenyl)butanoic acid 38 showed affinity for GABAB receptors. The conformationally restricted analogues of Baclofen, namely 1-(aminomethyl)-5-chloro-2,3-dihydro-1H-indene-1-acetic acid 39 and (1R,2S)-2-amino- methyl-2-(4′-chloro-phenyl)-cyclopropane-carboxylic acid 40 30 were surprisingly found inactive as GABAB ligands in the binding assay. Phosphinic acid derivatives 3-aminopropyl-phosphinic acid (3-APPA, CGP27492) 41 and its methyl homologue 3-aminopropyl-methyl-phosphinic acid (3-APMPA, CGP35024) 42 are more potent than the other active isomers of baclofen. The fluorine atoms of 3- aminopropyl-(difluromethyl)-phosphinic acid (CGP47656) 43 possess high affinity to GABAB receptors with partial agonist activity. Compound 44 show moderate activity while compound 45 show about one-third the activity of racemic Baclofen.31 In 1991, Kristiansen and Fjalland reported that the (R)-4-amino-3-hydroxybutanoic acid (3-OH- GABA) 46 acts as a GABAB agonist at ileal GABAB receptors. (R)-5-amino-3-(4′- chloro-phenyl)-pentanoic acid 47 and (S)-5-amino-3-(4′-chloro-phenyl)-pentanoic acid 48 show somewhat less activity than Baclofen32 (Figure-8). Figure-8 20 The development of selective GABAB receptor antagonists with increasing receptor affinity and potency play an important role in establishing the significance and structure of the GABAB receptor. Some GABAB receptor antagonists are shown in Figure-9. Figure-9: GABAB receptor antagonists. Allosteric modulators may delay dissociation by stabilizing the bound-agonist state or act as subtype-selective enhancers of agonist binding and promote receptor G protein coupling. 2,6-di-tert-butyl-4-(3hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) 59 was identified as a positive modulator for GABAB receptor. N-(3,3- diphenyl-propyl)-α-methyl-benzylamine (fendiline)