3- and 5-Isoxazolol zwitterions: an ab initio molecular orbital study relating to GABA agonism and antagonism (original) (raw)
Structure and molecular modeling of GABAA receptor antagonists
Journal of Medicinal Chemistry, 1992
The recently described potent and selective GABAA antagonist SR 95531 (gabazine) is compared to six other GABAA antagonists: (+)-bicuculline, (-)-securinine, (+)-tubocurarine, iso-THAZ, R-5135, and pitrazepine. Starting from ab initio molecular orbital calculations performed on crystal atomic coordinates, attempts were made to identify in each structure the functional groups that are involved in receptor recognition and binding. A molecular modeling study revealed that (a) all compounds possess accessible cationic and anionic sites separated by an 4.6-5.2 A intercharge distance, (b) the antagonistic nature of the compounds can be explained by the presence of additional binding sites, (c) the correct spatial orientation of the additional binding sites is crucial for GABAA selectivity, and (d) the criteria determining the potency of the antagonist effect are an accurate intercharge distance (>5 A) and the existence of hydrogen-bonding functionalities on one of the additional ring system. The presented pharmacophore accounts also for the inactivity of closely related compounds such as (-)-bicuculline, adlumidine, virosecurinine, allosecurinine, and the 4,6-diphenyl analogue of gabazine. (3) Bourguignon, J. J.; Schlewer, G.; Melikian, A.; Chantreux, D.; Molimard, J. C.; Heaulme, M.; Chambon, J. P.; BiziBre, K.; Wermuth, C. G. Aminopyridazines: Derivatives of SR 95103, structure-activity relationships. Pharmacologist 1985,27,518. (4) Wermuth, C. G.; Bourguignon, J. J.; Schlewer, G., Gies, J. P.; Schoenfelder, A.; Melikian, A.; Bouchet, M. J.; Chantreux, D.; Moliiard, J. C.; Heaulme, M.; Chambon, J. P.; BiziBre, K. Synthesis and StructureActivity Relationships of a Series of Aminopyridazine Derivatives of gamma-Aminobutyric Acid Acting as Selective GABA-A Antagonists. J. Med. Chem. 1987, 30, 239-249. (5) Heaulme, M.; Chambon, J. P.; Leyris, R.; Molimard, J. C.; Wermuth, C. G.; BiziBre, K. Biochemical Characterization of the Interaction of Three Pyridazinyl-GABA Derivatives with the GABAA Receptor Site. Brain Res. 1986, 384, 224-231. Chart 111. Putative Active Conformations of the GABAA Antagonists at Their Receptor Site Comoound 1 Gabazine Pitrazepine (-) -Securinine 60. THAZ (+) . Tubocurarine (+) -Bicuculline the GABAA receptor). In the second class, we selected molecules which are weaker antagonists, with ICM values Michaud, J. C.; Mienville, J. M.; Chambon, J. P.; BiziBre, K. Interactions between three pyridazinyl-GABA derivatives and central GABA and glycine receptors in the rat. An in vi00 microiontophoretic study. Neuropharmacology 1986, 25, Santucci, V.; Fournier, M.; Chambon, J. P.; BiziBre, K. Electroencephalographic study of SR 95103, a GABAA antagonist: Interaction with inhibitory amino acids and muscimol. Eur. J. Pharmacol. 1985,114, 219-222. Melikian, A.; Schlewer, G.; Hurt, S.; Chantreux, D.; Wermuth, C. G. Synthesis of tritiium-labelled 2-(3'-carboxypropyl)-3-imino-6 para-methoxy phenyl-2,3-dihydropyridazine ( [sH] SR 95531). J. Labeled Compd. Radiopharm. 1987,24, 267-274. Du Pont, NEN Products, Boston, MA 02118. Heaulme, M.; Chambon, J. P.; Leyris, R.; Wermuth, C. G.; BiziBre, K. Specific binding of a phenyl-pyridazinium derivative endowed with GABAA receptor antagonist activity to rat brain. Neuropharmacology 1986,25,1279-1283. Heaulme, M.; Chambon, J. P.; Leyris, R.; Wermuth, C. G.; BiziBre, K. Characterization of the Binding of [3H]SR 95531, a GABAA Antagonist to Rat Brain Membranes. J. Neurochem. 1987,48, 1667-1686. Steward, E. G.; Borthwick, P. W.; Clarke, G. R.; Warner, D. Agonism and antagonism of gamma-aminobutyric acid. Nature (London) 1975,256, 600-602. Wermuth, C. G.; Rognan, D. Modeling of Antagonists of the GABA-A Receptor. Actual Chim. ThBr. 1987, 14, 215-233. Boulanger, T.; Vercauteren, D. P.; Durant, F.; Andr6, J. M. 3and 5-Isoxazolol Zwitterions: An ab initio Molecular Orbital Study relating to GABA Agonism and Antagonism, J. Theor. Biol. 1987, 127, 479-489. Pooler, C. W.; Steward, E. G. Structural factors governing agonist and antagonist activity in the GABAA system.
Journal of Medicinal Chemistry, 2005
A series of new 1,2-diphenylimidazole derivatives (1a-x) were synthesized and evaluated for their ability to potentiate γ-aminobutyric acid (GABA)-evoked currents in Xenopus laevis oocytes expressing recombinant human GABA A receptors. Many of these compounds enhanced GABA action with potencies (EC 50) 0.19-19 µM) and efficacies (maximal efficacies of up to 640%) similar to or greater than those of anesthetics such as etomidate, propofol, and alphaxalone. Structure-activity relationship analysis revealed that the presence of an ester moiety in the imidazole ring was required for full agonist properties, while modifications made in the phenyl rings affected potency and efficacy, with ethyl 2-(4-bromophenyl)-1-(2,4-dichlorophenyl)-1H-4-imidazolecarboxylate showing the highest potency. These compounds potentiated the [ 3 H]-GABA binding to rat brain membranes, suggesting a site of interaction different from that of GABA. As for etomidate, mutation of asparagine-265 in the 2 subunit of the GABA A receptor into serine reduced the ability of derivative 1i to modulate the GABA function.
European Journal of Pharmacology: Molecular Pharmacology, 1994
The effects of pentylenetetrazol and bicyclic 7-butyrolactones of similar stereostructures were studied on the convulsant and benzodiazepine binding sites and chloride ionophore activity of the y-aminobutyric acid (GABA A) receptor-complex. Bicyclic y-butyrolactones displayed millimolar IC50 values and low stereoselectivities on [35S]t-butylbicyclophosphorothionate (TBPS) binding to the convulsant sites in synaptosomal membranes of rat forebrains. Ring saturation of bicyclic 7-butyrolactones decreased their IC50 values by one order of magnitude. The IC50 values of saturated bicyclic y-butyrolactones and pentylenetetrazol were increased by GABA versus its antagonist R 5135 (3a-hydroxy-16-imino-5fl,17-aza-androstan-ll-one). A bicyclic y-butyrolactone and pentylenetetrazol accelerated the dissociation of [35S]TBPS, displaced [3H]flumazenil binding in two phases and blocked the muscimol-elicited chloride currents in patch-clamped cortical neurones in culture in a similar manner. These similar effects on binding and ionophore function support their common modes of action on the GABA A receptor-ionophore complex.
Neurochemistry International, 2003
The system of GABA transporters in neural cells constitutes an efficient mechanism for terminating inhibitory GABAergic neurotransmission. As such these transporter are important therapeutical targets in epilepsy and potentially other neurological diseases related to the GABA system. In this study a number of analogs of 3-hydroxy-4-amino-4,5,6,7-tetrahydro-1,2-benzisoxazol (exo-THPO), a promising lead structure for inhibitors of GABA uptake were investigated. It was found that the selectivity of N-acetyloxyethyl-exo-THPO for inhibition of the astroglial GABA uptake system was 10-fold as compared to inhibition of the neuronal GABA uptake system. Selectivity in this magnitude may provide potent anti-convulsant activity as has recently been demonstrated with the likewise glia-selective GABA uptake inhibitor, N-methyl-exo-THPO. In contrast to the competitive inhibition of GABA uptake exhibited by N-substituted analogs of 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol (THPO), nipecotic acid, and guvacine, N-4,4-diphenyl-3-butenyl(DPB)-N-methyl-exo-THPO and 4-phenylbutyl-exo-THPO exhibited non-competitive type inhibition kinetics. The lipophilic character of a number of GABA analogs was concluded by far to constitute the determining factor for the potency of these compounds as inhibitors of GAT1-mediated uptake of GABA. This finding underscores the complexity of the pharmacology of the GABA transport system, since these non-competitive inhibitors are structurally very similar to some competitive GABA uptake inhibitors. Whether these structure-activity relationships for inhibition of GABA uptake may provide sufficient information for the development of new structural leads and to what extent these compounds may be efficient as therapeutical anti-convulsant agents remain to be elucidated.
Neurochemicals for the Investigation of GABAC Receptors
Neurochemical Research, 2010
GABA C receptors are being investigated for their role in many aspects of nervous system function including memory, myopia, pain and sleep. There is evidence for functional GABA C receptors in many tissues such as retina, hippocampus, spinal cord, superior colliculus, pituitary and the gut. This review describes a variety of neurochemicals that have been shown to be useful in distinguishing GABA C receptors from other receptors for the major inhibitory neurotransmitter GABA. Some selective agonists (including (?)-CAMP and 5-methyl-IAA), competitive antagonists (such as TPMPA, (±)-cis-3-ACPBPA and aza-THIP), positive (allopregnanolone) and negative modulators (epipregnanolone, loreclezole) are described. Neurochemicals that may assist in distinguishing between homomeric q1 and q2 GABA C receptors (2-methyl-TACA and cyclothiazide) are also covered. Given their less widespread distribution, lower abundance and relative structural simplicity compared to GABA A and GABA B receptors, GABA C receptors are attractive drug targets.