Potent 4-arylalkyl-substituted 3-isothiazolol GABA(A) competitive/noncompetitive antagonists: synthesis and pharmacology

The GABA(A) agonists muscimol (1), 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP, gaboxadol, 3), and the partial GABA(A) agonist 5-(4-piperidyl)-3-isoxazolol (4-PIOL, 6a) and their respective 3-isothiazolol analogues thiomuscimol (2), thio-THIP (4), and thio-4-PIOL (7a) are ligands at the GABA(A) orthosteric (recognition) site. The structure-activity relationships (SARs) between these structures are key elements of a 3D-pharmacophore model for GABA(A) agonists and competitive antagonists [Fr?lund, B.; J?rgensen, A. T.; Tagmose, L.; Stensb?l, T. B.; Vestergaard, H. T.; Engblom, C.; Kristiansen, U.; Sanchez, C.; Krogsgaard-Larsen, P.; Liljefors, T. J. Med. Chem. 2002, 45, 2454-2468]. Prompted by this model, we now report the synthesis and SAR of a series of analogues of 7a, in which the 4-position of the 3-isothiazolol was substituted by alkyl or bulky aromatic groups such as naphthylmethyl and diphenylalkyl groups (7b-h). The compounds have been pharmacologically characterized using receptor binding assays and two-electrode voltage-clamped Xenopus oocytes expressing alpha1beta3gamma2S- and alpha4beta3delta-containing receptors. The compounds show SARs comparable with those of 6b-h but are generally 5-15 times more potent. The 2-naphthylmethyl, the 1-bromo-2-naphthylmethyl, and the 3,3-diphenylpropyl analogues, compounds 7e, 7f, and 7h, respectively, show affinity in the low-nanomolar range (K(i) 2-10 nM). Interestingly, 7e and 7h exhibited a mixed antagonist profile consisting of a noncompetitive component in the picomolar range and a competitive component at concentrations above 1 nM. This unique profile was shown not to be due to either use dependence or kinetic effects. This antagonist profile of 7e and 7h was particularly pronounced at alpha4beta3delta-containing GABA(A) receptors, which showed three- and 10-fold selectivity for 7h and 6h, respectively.     

Novel class of potent 4-arylalkyl substituted 3-isoxazolol GABA(A) antagonists: synthesis,pharmacology, and molecular modeling

A number of analogues of the low-efficacy partial GABA(A) agonist 5-(4-piperidyl)-3-isoxazolol (4-PIOL, 5), in which the 4-position of the 3-isoxazolol ring was substituted by different groups, were synthesized and tested as GABA(A) receptor ligands. Substituents of different size and structural flexibility such as alkyl, phenylalkyl, diphenylalkyl, and naphthylalkyl were explored. Pharmacological characterization of the synthesized compounds was carried out using receptor binding assays and by electrophysiological experiments using whole-cell patch-clamp techniques. Whereas none of these compounds significantly affected GABA(B) receptor sites or GABA uptake, they did show affinity for the GABA(A) receptor site. While alkyl or benzyl substitution, compounds 7a-h, provided receptor affinities comparable with that of 5 (K(i) = 9.1 microM), diphenylalkyl and naphthylalkyl substitution, as in compounds 7m-t, resulted in a dramatic increase in affinity relative to 5. The 3,3-diphenylpropyl and the 2-naphthylmethyl analogues, compounds 7s and 7m, respectively, showed the highest affinities of the series (K(i) = 0.074 microM and K(i) = 0.049 microM). In whole-cell patch-clamp recordings from cultured cerebral cortical neurons, all of the tested compounds were able to inhibit the effect of the specific GABA(A) agonist isoguvacine (1), compounds 7m and 7s showing antagonist potency (IC(50) = 0.37 microM and IC(50) = 0.02 microM) comparable with or markedly higher than that of the standard GABA(A) antagonist 4 (IC(50) = 0.24 microM). Highly potent convulsant activity was demonstrated in mice with compounds 7m (ED(50) = 0.024 micromol/kg) and 7s (ED(50) = 0.21 micromol/kg) after intracerebroventricular administration, whereas no effects were found after subcutaneous administration. According to a previously proposed pharmacophore model for GABA(A) receptor agonists, a receptor cavity in the vicinity of the 4-position of the 3-isoxazolol ring in 4-PIOL exists. A molecular modeling study, based on compounds 7o,m,l,q,s, was performed to explore the dimensions and other properties of the receptor cavity. This study demonstrates the importance of the arylalkyl substituents in 7m and 7s and the considerable dimensions of this proposed receptor cavity.     

4-aryl-5-(4-piperidyl)-3-isoxazolol GABAA antagonists: synthesis, pharmacology, and structure-activity relationships

A series of 4-aryl-5-(4-piperidyl)-3-isoxazolol GABAA antagonists have been synthesized and pharmacologically characterized. The meta-phenyl-substituted compounds 9k and 9m and the para-phenoxy-substituted compound 9l all display high affinities (Ki=10-70 nM) and antagonist potencies in the low nanomolar range (Ki=9-10 nM). These potencies are significantly higher than those of previously reported 4-PIOL antagonists and considerably higher than that of the standard GABAA antagonist SR 95531.     

Selective antagonists at group I metabotropic glutamate receptors: synthesis and molecular pharmacology of 4-aryl-3-isoxazolol amino acids

Homologation of (S)-glutamic acid (Glu, 1) and Glu analogues has previously provided ligands with activity at metabotropic Glu receptors (mGluRs). The homologue of ibotenic acid (7), 2-amino-3-(3-hydroxy-5-isoxazolyl)propionic acid (HIBO, 8), and the 4-phenyl derivative of 8, compound 9a, are both antagonists at group I mGluRs. Here we report the synthesis and molecular pharmacology of HIBO analogues 9b-h containing different 4-aryl substituents. All of these compounds possess antagonist activity at group I mGluRs but are inactive at group II and III mGluRs.     

4-quinolone derivatives: high-affinity ligands at the benzodiazepine site of brain GABA A receptors. synthesis, pharmacology, and pharmacophore modeling

The 3-ethoxycarbonyl-4-quinolone compound 1 has previously been identified via a database search as an interesting lead compound for ligand binding at the benzodiazepine site of GABA(A) receptors (Kahnberg et al. J. Mol. Graphics Modelling 2004, 23, 253-261). Pharmacophore-guided optimization of this lead compound yielded a number of high-affinity ligands for the benzodiazepine site including compounds 20 and 23-25 displaying sub-nanomolar affinities. A few of the compounds have been tested on the alpha(1)beta(2)gamma(2S) and alpha(3)beta(2)gamma(2S) GABA(A) receptor subtypes, and two of the compounds (5 and 19) display selectivity for alpha(1)- versus alpha(3)-containing receptors by a factor of 22 and 27, respectively. This selectivity for alpha(1)beta(2)gamma(2S) is in the same range as that for the well-known alpha(1) subunit selective compound zolpidem.     

New serotonin 5-HT(2A), 5-HT(2B), and 5-HT(2C) receptor antagonists: synthesis, pharmacology, 3D-QSAR, and molecular modeling of (aminoalkyl)benzo and heterocycloalkanones.

A series of 52 conformationally constrained butyrophenones have been synthesized and pharmacologically tested as antagonists at 5-HT(2A), 5-HT(2B), and 5-HT(2C) serotonin receptors, useful for dissecting the role of each 5-HT(2) subtype in pathophysiology. These compounds were also a consistent set for the identification of structural features relevant to receptor recognition and subtype discrimination. Six compounds were found highly active (pK(i) > 8.76) and selective at the 5-HT(2A) receptor vs 5-HT(2B) and/or 5-HT(2C) receptors. Piperidine fragments confer high affinity at the 5-HT(2A) receptor subtype, with benzofuranone- and thiotetralonepiperidine as the most selective derivatives over 5-HT(2C) and 5-HT(2B) receptors, respectively; K(i) (2A/2C) and/or K(B) (2A/2B) ratios greater than 100 were obtained. Compounds showing a more pronounced selectivity at 5-HT(2A)/5-HT(2C) than at 5-HT(2A)/5-HT(2B) bear 6-fluorobenzisoxazolyl- and p-fluorobenzoylpiperidine moieties containing one methylene bridging the basic piperidine to the alkanone moiety. An ethylene bridge between the alkanone and the amino moieties led to ligands with higher affinities for the 5-HT(2B) receptor. Significant selectivity at the 5-HT(2B) receptor vs 5-HT(2C) was observed with 1-1[(1-oxo-1,2,3,4-tetrahydro-3-naphthyl)methyl]-4-[3-(p-fluorobenzoyl)propyl]piperazine (more than 100-fold higher). Although piperidine fragments also confer higher affinity at 5-HT(2C) receptors, only piperazine-containing ligands were selective over 5-HT(2A). Moderate selectivity was observed at 5-HT(2C) vs 5-HT(2B) (10-fold) with some compounds bearing a 4-[3-(6-fluorobenzisoxazolyl)]piperidine moiety in its structure. Molecular determinants for antagonists acting at 5-HT(2A) receptors were identified by 3D-QSAR (GRID-GOLPE) studies. Docking simulations at 5-HT(2A) and 5-HT(2C) receptors suggest a binding site for the studied type of antagonists (between transmembrane helices 2, 3, and 7) different to that of the natural agonist serotonin (between 3, 5, and 6).     

GABA(A) receptor channel pharmacology

GABA(A) receptor channels are ubiquitous in the mammalian central nervous system mediating fast inhibitory neurotransmission by becoming permeant to chloride ions in response to GABA. The emphasis of this review is on the rich chemical diversity of ligands that influence GABA(A) receptor function. Such diversity provides many avenues for the design and development of new chemical entities acting on GABA(A) receptors. There is also a significant diversity of GABA(A) receptor subtypes composed of different protein subunits. The discovery of subtype specific agents is a major challenge in the continuing development of GABA(A) receptor pharmacology. Leads for the discovery of new chemical entities that influence GABA(A) receptors come from using recombinant GABA(A) receptors of known subunit composition as has been elegantly demonstrated by the refining of benzodiazepine actions with alpha1 subunit preferring agents showing sedative properties but not anxiolytic properties. The most recent advances in the therapeutic use of agents acting on GABA(A) receptors concern the promotion of sound sleep. Many herbal medicines are used to promote sleep and many of their active ingredients include flavonoids and terpenoids known to modulate GABA(A) receptor function.     

Medicinal chemistry and molecular pharmacology of GABA(C) receptors

GABA(C) receptors belong to the nicotinicoid superfamily of ionotropic receptors that include nicotinic acetylcholine receptors, bicuculline-sensitive GABA(A) receptors, strychnine-sensitive glycine receptors and 5HT3 serotonin receptors. The GABA(C) receptor concept arose from medicinal chemical studies of a conformationally restricted analog of GABA. Receptors matching the predicted properties of GABA(C) receptors were cloned from the retina. Post cloning studies revealed the unique physiology and pharmacology of these relatively simple homomeric receptors. Three subtypes of GABA(C) receptors have been cloned from mammalian sources and pharmacological differences between the rho1, rho2 and rho3 GABA(C) receptors have been described. There is evidence for functional GABA(C) receptors in the retina, spinal cord, superior colliculus, pituitary and the gut and their involvement in vision, aspects of memory and sleep-waking behaviour. This review concentrates on the medicinal chemistry and molecular pharmacology of GABA(C) receptor subtypes emphasising possible new investigational tools with which to investigate further GABA(C) receptor function. The most useful currently available ligands that show some GABA(C) receptor subtype selectivity are TPMPA, P4PMA, imidazole-4-acetic acid, 2-methyl-TACA and (+/-)-TAMP.     

Synthesis and pharmacology of 3-isoxazolol amino acids as selective antagonists at group I metabotropic glutamic acid receptors

Using ibotenic acid (2) as a lead, two series of 3-isoxazolol amino acid ligands for (S)-glutamic acid (Glu, 1) receptors have been developed. Whereas analogues of (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid [AMPA, (RS)-3] interact selectively with ionotropic Glu receptors (iGluRs), the few analogues of (RS)-2-amino-3-(3-hydroxy-5-isoxazolyl)propionic acid [HIBO, (RS)-4] so far known typically interact with iGluRs as well as metabotropic Glu receptors (mGluRs). We here report the synthesis and pharmacology of a series of 4-substituted analogues of HIBO. The hexyl analogue 9 was shown to be an antagonist at group I mGluRs. The effects of 9 were shown to reside exclusively in (S)-9 (K(b) = 30 microM at mGlu(1) and K(b) = 61 microM at mGlu(5)). The lower homologue of 9, compound 8, showed comparable effects at mGluRs, but 8 also was a weak agonist at the AMPA subtype of iGluRs. Like 9, the higher homologue, compound 10, did not interact with iGluRs, but 10 selectively antagonized mGlu(1) (K(b) = 160 microM) showing very weak antagonist effect at mGlu(5) (K(b) = 990 microM). The phenyl analogue 11 turned out to be an AMPA agonist and an antagonist at mGlu(1) and mGlu(5), and these effects were shown to originate in (S)-11 (EC(50) = 395 microM, K(b) = 86 and 90 microM, respectively). Compound 9, administered icv, but not sc, was shown to protect mice against convulsions induced by N-methyl-D-aspartic acid (NMDA). Compounds 9 and 11 were resolved using chiral HPLC, and the configurational assignments of the enantiomers were based on X-ray crystallographic analyses.     

Pathophysiology and pharmacology of GABA(A) receptors

By controlling spike timing and sculpting neuronal rhythms, inhibitory interneurons play a key role in brain function. GABAergic interneurons are highly diverse. The respective GABA(A) receptor subtypes, therefore, provide new opportunities not only for understanding GABA-dependent pathophysiologies but also for targeting of selective neuronal circuits by drugs. The pharmacological relevance of GABA(A) receptor subtypes is increasingly being recognized. A new central nervous system pharmacology is on the horizon. The development of anxiolytic drugs devoid of sedation and of agents that enhance hippocampus-dependent learning and memory has become a novel and highly selective therapeutic opportunity.     

(3-Aminocyclopentyl)methylphosphinic acids: novel GABA(C) receptor antagonists

Our understanding of the role GABA(C) receptors play in the central nervous system is limited due to a lack of specific ligands. Here we describe the pharmacological effects of (+/-)-cis-3- and (+/-)-trans-3-(aminocyclopentyl)methylphosphinic acids ((+/-)-cis- and (+/-)-trans-3-ACPMPA) as novel ligands for the GABA(C) receptor showing little activity at GABA(A) or GABA(B) receptors. (+/-)-cis-3-ACPMPA has similar potency to (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA) at human recombinant rho1 (K(B)=1.0+/-0.2microM) and rat rho3 (K(B)=5.4+/-0.8microM) but is 15 times more potent than TPMPA on human recombinant rho2 (K(B)=1.0+/-0.3microM) GABA(C) receptors expressed in Xenopus oocytes. (+/-)-cis- and (+/-)-trans-3-ACPMPA are novel lead compounds for developing into more potent and selective GABA(C) receptor antagonists with increased lipophilicity for in vivo studies.     

Synthesis,molecular modeling studies,and pharmacological activity of selective A(1) receptor antagonists

We present a combined computational study aimed at identifying the three-dimensional structural properties required for different classes of compounds to show antagonistic activity toward the A(1) adenosine receptor (AR). Particularly, an approach combining pharmacophore mapping, molecular alignment, and pseudoreceptor generation was applied to derive a hypothesis of the interaction pathway between a set of A(1) AR antagonists taken from the literature and a model of the putative A(1) receptor. The pharmacophore model consists of seven features and represents an improvement of the N(6)-C8 model, generally reported as the most probable pharmacophore model for A(1) AR agonists and antagonists. It was used to build up a pseudoreceptor model able to rationalize the relationships between structural properties and biological data of, and external to, the training set. In fact, to further assess its statistical significance and predictive power, the pseudoreceptor was employed to predict the free energy of binding associated with compounds constituting a test set. While part of these molecules was also taken from the literature, the remaining compounds were designed and synthesized by our research group. All of the new compounds were tested for their affinity toward A(1), A(2a), and A(3) AR, showing interesting antagonistic activity and A(1) selectivity.     

GABA(A)-receptor subtypes: a new pharmacology.

The GABA(A) receptor is a pluripotent drug target mediating anxiolytic, sedative, anticonvulsant, muscle relaxant and amnesic activity. These drug actions have now been attributed to defined receptor subtypes. Thus, precise guidelines are available for the development of novel drugs with more selective action and less side effects than those currently in clinical use.     

Synthesis and pharmacology of a series of 3- and 4-(phosphonoalkyl)pyridine- and -piperidine-2-carboxylic acids. Potent N-methyl-D-aspartate receptor antagonists

We recently prepared a series of 3- and 4-(phosphonoalkyl)pyridine- and -piperidine-2-carboxylic acids as antagonists of neurotransmission at N-methyl-D-aspartate (NMDA) preferring receptors. NMDA antagonists may prove to be useful therapeutic agents, for instance, as anticonvulsants, in the treatment of neurodegenerative disorders such as Alzheimer's disease and in the prevention of neuronal damage that occurs during cerebral ischemia. The compounds prepared were evaluated for their ability to displace [3H]CPP binding (an assay shown to be selective for compounds that bind at the NMDA receptor) and for their ability to block NMDA-induced lethality in mice (an assay that is also specific for competitive and noncompetitive NMDA antagonists). Two of the compounds, cis-4-(phosphonomethyl)piperidine-2-carboxylic acid (11a) and cis-4-(3-phosphonoprop-1-yl)piperidine-2-carboxylic acid (11c) proved to be potent NMDA antagonists. 11a and 11c displaced [3H]CPP binding with IC50's of 95 and 120 nM, respectively, and both protected mice from NMDA-induced lethality, with MEDs (minimum effective dose, the dose at which three of the five animals tested survived) of 10 and 40 mg/kg ip, respectively. The rest of the compounds prepared were weakly active or inactive in these assays. The pattern of activity observed for this series parallels that observed for the acyclic series of omega-phosphono-alpha-amino acids, where AP5 and AP7 possessed NMDA antagonist activity while AP6 and AP8 were inactive. Reduction of conformational mobility by incorporation of the piperidine ring led to enhanced potency relative to the acyclic analogues.     

5-HT(4) receptors: history, molecular pharmacology and brain functions

Twenty years ago, we started the characterization of a 5-HT receptor coupled to cAMP production in neurons. This receptor obviously had a different pharmacology to the other 5-HT receptors described at that time, i.e. the 5-HT₁, 5-HT₂, 5-HT₃ receptors. We proposed to name it the 5-HT₄ receptor. Nowadays, 5-HT₄ receptors are one of the most studied GPCRs belonging to the “rhodopsin” family. Thanks to the existence of a great variety of ligands with inverse agonist, partial agonist, agonist and antagonist profiles, the pharmacological and physiological properties of this receptor are beginning to emerge. Although some 5-HT₄ partial agonists have been on the market for gastro-intestinal pathologies, 5-HT₄ receptor drugs have still to be commercialized for brain disorders. However, since 5-HT₄ receptors have recognized effects on memory, depression and feeding in animal models, there is still hope for a therapeutic destiny of this interesting target in brain disorders.     

Selective inhibitors of glial GABA uptake: synthesis, absolute stereochemistry, and pharmacology of the enantiomers of 3-hydroxy-4-amino-4,5,6,7-tetrahydro-1,2-benzisoxazole (exo-THPO) and analogues

3-Methoxy-4,5,6,7-tetrahydro-1,2-benzisoxazol-4-one (20a), or the corresponding 3-ethoxy analogue (20b), and 3-chloro-4,5,6, 7-tetrahydro-1,2-benzisothiazol-4-one (51) were synthesized by regioselective chromic acid oxidation of the respective bicyclic tetrahydrobenzenes 19a,b and 50, and they were used as key intermediates for the syntheses of the target zwitterionic 3-isoxazolols 8-15 and 3-isothiazolols 16 and 17, respectively. These reaction sequences involved different reductive processes. Whereas (RS)-4-amino-3-hydroxy-4,5,6,7-tetrahydro-1,2-benzisoxazole (8, exo-THPO) was synthesized via aluminum amalgam reduction of oxime 22a or 22b, compounds 9, 11-13, and 15-17 were obtained via reductive aminations. Compound 10 was synthesized via N-ethylation of the N-Boc-protected primary amine 25. The enantiomers of 8 were obtained in high enantiomeric purities (ee >/= 99.1%) via the diastereomeric amides 32 and 33, synthesized from the primary amine 23b and (R)-alpha-methoxyphenylacetyl chloride and subsequent separation by preparative HPLC. The enantiomers of 9 were prepared analogously from the secondary amine 27. On the basis of X-ray crystallographic analyses, the configuration of oxime 22a was shown to be E and the absolute configurations of (-)-8 x HCl and (+)-9 x HBr were established to be R. The effects of the target compounds on GABA uptake mechanisms in vitro were measured using a rat brain synaptosomal preparation and primary cultures of mouse cortical neurons and glia cells (astrocytes). Whereas the classical GABA uptake inhibitor, (R)-nipecotic acid (2), nonselectively inhibits neuronal (IC(50) = 12 microM) and glial (IC(50) = 16 microM) GABA uptake and 4,5,6,7-tetrahydroisoxazolo?4,5-cpyridin-3-ol (1, THPO) shows some selectivity for glial (IC(50) = 268 microM) versus neuronal (IC(50) = 530 microM) GABA uptake, exo-THPO (8) was shown to be more potent as an inhibitor of glial (IC(50) = 200 microM) rather than neuronal (IC(50) = 900 microM) GABA uptake. This selectivity was more pronounced for 9, which showed IC(50) values of 40 and 500 microM as an inhibitor of glial and neuronal GABA uptake, respectively. These effects of 8 and 9 proved to be enantioselective, (R)-(-)-8 and (R)-(+)-9 being the active inhibitors of both uptake systems. The selectivity of 9 as a glial GABA uptake inhibitor was largely lost by replacing the N-methyl group of 9 by an ethyl group, compound 10 being an almost equipotent inhibitor of glial (IC(50) = 280 microM) and neuronal (IC(50) = 400 microM) GABA uptake. The remaining target compounds, 11-17, were very weak or inactive as inhibitors of both uptake systems. Compounds 9-13 and 15 were shown to be essentially inactive against isoniazide-induced convulsions in mice after subcutaneous administration. The isomeric pivaloyloxymethyl derivatives of 9, compounds 43 and 44, were synthesized and tested as potential prodrugs in the isoniazide animal model. Both 43 (ED(50) = 150 micromol/kg) and 44 (ED(50) = 220 micromol/kg) showed anticonvulsant effects, and this effect of 43 was shown to reside in the (R)-(+)-enantiomer, 45 (ED(50) = 44 micromol/kg). Compound 9 also showed anticonvulsant activity when administered intracerebroventricularly (ED(50) = 59 nmol).     

Synthesis and pharmacology of 3-aryl-5,6-dihydro-6-oxo-1(4H)-pyridazineacetic acid derivatives.

The title compounds were prepared by alkylation of 6-aryl-4,5-dihydro-3(2H)-pyridazinones with esters of alpha-bromoacetic acid. Hydrolysis of these esters afforded the corresponding carboxylic acids which were coupled with various amines yielding 6-oxo-1(4H)-pyridazineacetamides. A number of these derivatives showed weak anticonvulsant and weak analgesic activities, while nearly all displayed a sedative profile.     

GABA uptake inhibitors. Design, molecular pharmacology and therapeutic aspects

In the mid seventies a drug design programme using the Amanita muscaria constituent muscimol (7) as a lead structure, led to the design of guvacine (23) and (R)-nipecotic acid (24) as specific GABA uptake inhibitors and the isomeric compounds isoguvacine (10) and isonipecotic acid (11) as specific GABAA receptor agonists. The availability of these compounds made it possible to study the pharmacology of the GABA uptake systems and the GABAA receptors separately. Based on extensive cellular and molecular pharmacological studies using 23, 24, and a number of mono- and bicyclic analogues, it has been demonstrated that neuronal and glial GABA transport mechanisms have dissimilar substrate specificities. With GABA transport mechanisms as pharmacological targets, strategies for pharmacological interventions with the purpose of stimulating GABA neurotransmission seem to be (1) effective blockade of neuronal as well as glial GABA uptake in order to enhance the inhibitory effects of synaptically released GABA, or (2) selective blockade of glial GABA uptake in order to increase the amount of GABA taken up into, and subsequently released from, nerve terminals. The bicyclic compound (R)-N-Me-exo-THPO (17) has recently been reported as the most selective glial GABA uptake inhibitor so far known and may be a useful tool for further elucidation of the pharmacology of GABA transporters. In recent years, a variety of lipophilic analogues of the amino acids 23 and 24 have been developed, and one of these compounds, tiagabine (49) containing (R)-nipecotic acid (24) as the GABA transport carrier-recognizing structure element, is now marketed as an antiepileptic agent.