SKF 97541

The GABA(B) antagonist CGP 52432 attenuates the stimulatory effect of the GABA(B) agonist SKF 97541 on luteinizing hormone secretion in the male sheep.[Pubmed:11976401]

Exp Biol Med (Maywood). 2002 May;227(5):315-20.

The objectives of this study were to determine if the gamma-aminobutyric acid (GABA)(B) agonist, 3-aminopropyl (methyl) phosphinic acid (SKF97541), would increase luteinizing hormone (LH) secretion when infused by microdialysis into the medial basal hypothalamus (MBH) of the castrated ram, and to determine if the action of SKF97541 would be attenuated by co-infusion of the GABA(B) antagonist CGP52432. Initial experiments established that infusion of SKF alone, at concentrations as low as 5 microM, increased mean LH, LH pulse amplitude, and in some cases, pulse interval. In the last experiment, animals were treated with artificial cerebrospinal fluid (CSF) alone, SKF alone (30 microM), 3-[[(3, 4-dichlorophenol) methyl] amino] propyl] diethoxymethyl) phosphinic acid (CGP) alone (500 microM), or SKF plus CGP. SKF increased both mean LH and LH pulse amplitude as compared with CSF. CGP alone had no significant effect on LH, but it attenuated the effect of SKF on mean LH. These observations indicate that the stimulatory effects of GABA(B) agonists on LH pulse patterns are mediated through GABA(B) receptors and provide further evidence that GABA(B) receptors located in the MBH can regulate pulsatile GnRH-LH release.

Electrophysiological actions of GABAB agonists and antagonists in rat dorso-lateral septal neurones in vitro.[Pubmed:8799569]

Br J Pharmacol. 1996 Jun;118(4):961-7.

1. The actions of GABAB-receptor agonists and antagonists on rat dorso-lateral septal neurones in vitro were recorded with intracellular microelectrodes. 2. In the presence of 1 microM tetrodotoxin to prevent indirect neuronal effects caused by action potential-dependent neurotransmitter release, bath application of baclofen (0.1-30 microM) or SK&F 97541 (0.01-3 microM) evoked concentration-dependent hyperpolarizations which reversed close to the potassium equilibrium potential; the EC50S were 0.55 and 0.05 microM, respectively. No significant desensitization was observed during prolonged agonist exposure (< or = 10 min). 3. Hyperpolarizations induced by baclofen were antagonized in a competitive manner by the following GABAB-receptors antagonists (calculated pA2 values in parentheses): CGP 36742 (4.0), 2-OH saclofen (4.2), CGP 35348 (4.5), CGP 52432 (6.7) and CGP 55845A (8.3). Responses to SK&F 97541 were also antagonized by CGP 55845A (pA2 = 8.4). 4. The amplitude of the late, GABAB receptor-mediated inhibitory postsynaptic potential (i.p.s.p.) was reduced by the GABAB antagonists as follows (means +/- s.e.mean): CGP 55845A (1 microM) 91 +/- 5%, CGP 52432 (1 microM) 64 +/- 5%, CGP 35348 (100 microM) 82 +/- 5%, CGP 36742 (100 microM) 76 +/- 8%, and 2-OH saclofen (100 microM) 68 +/- 3%. 5. It is concluded that neurones in the rat dorso-lateral septal nucleus express conventional GABAB receptors, which are involved in the generation of slow inhibitory postsynaptic potentials. CGP 55845A is the most potent GABAB receptor antagonist described in this brain area.

Phosphinic acid analogues of GABA. 1. New potent and selective GABAB agonists.[Pubmed:7650684]

J Med Chem. 1995 Aug 18;38(17):3297-312.

The antispastic agent and muscle relaxant baclofen 1 is a potent and selective agonist for bicuculline-insensitive GABAB receptors. For many years efforts to obtain superior GABAB agonists were unsuccessful. We describe the syntheses and biological properties of two new series of GABAB agonists, the best compounds of which are more potent than baclofen in vitro and in vivo. They were obtained by replacing the carboxylic acid group of GABA or baclofen derivatives with either the phosphinic acid or the methylphosphinic acid residue. Surprisingly, ethyl- and higher alkylphosphinic acid derivatives of GABA yielded novel GABAB antagonists, which are described in part 2 of this series. Structure-activity relationships of the novel GABAB agonists are discussed with respect to their affinities to GABAB receptors as well as to their effects in many functional tests in vitro and in vivo providing new muscle relaxant drugs with significantly improved side effect profiles.

Electrophysiological characterization of potent agonists and antagonists at pre- and postsynaptic GABAB receptors on neurones in rat brain slices.[Pubmed:1964824]

Br J Pharmacol. 1990 Dec;101(4):949-57.

1. Intracellular recordings were made from neurons in striatum (caudate-putamen) and substantia nigra pars compacta in rat brain slices. Three GABAB agonists, baclofen, 3-aminopropylphosphinic acid (3-APPA) and 3-aminopropyl(methyl)phosphinic acid (SK&F 97541), depressed excitatory postsynaptic potentials (e.p.s.ps) mediated by glutamate in the striatum, and hyperpolarized neurones in the substantia nigra. The ability of 3-aminopropyl(diethyoxymethyl)phosphinic acid (CGP 35348), 3-aminopropyl (hexyl)phosphinic acid (3-APHPA) and phaclofen to antagonize these responses was assessed. 2. Striatal e.p.s.ps, studied in the presence of bicuculline (30 microns), were reduced in amplitude by 92% with 6,7-dinitroquinoxaline-2,3-dione (DNQX; 30 microns). These e.p.s.ps were depressed by up to 95% by SK&F 97541 and baclofen with EC50s of 0.092 microns and 1.25 microns respectively. The maximal effect of 3-APPA was 67% with an EC50 of 0.83 microns. Agonist concentration-effect data fitted a single-site logistic model. GABAB agonists were without effect on striatal neurone membrane potential, input resistance or depolarizations induced by applied glutamate. 3. The depression of striatal e.p.s.ps by SK&F 97541 was reversibly antagonized by CGP 35348, 3-APHPA and phaclofen with estimated equilibrium dissociation constants (KB) of 11.2 +/- 1.7 microns (n = 4), 13.3 +/- 0.4 microM (n = 3) and 405 +/- 43 microM (n = 3) respectively. CGP 35348 and 3-APHPA appeared to act competitively (Schild plot slopes of 0.99 and 1.01 respectively). 4. Nigral neurones were hyperpolarized by up to 25 mV by SK&F 97541 and baclofen with EC50s of 0.15 microns and 3.6 microns respectively. The maximum hyperpolarization by 3-APPA was only 84% that of the other agonists, with an EC50 of 9.0 microM. Agonist concentration-effect data fitted a single-site logistic model. 5. The SK&F 97541-induced hyperpolarization was reversibly antagonized by CGP 35348, 3-APHPA and phaclofen with estimated KBS of 17.6 + 4.4 (n = 3), 14.0 + 1.5 (n = 4), and >400 microM (n = 1) respectively. CGP 35348 appeared competitive (Schild plot slope of 0.99). Antagonists were also tested with baclofen as agonist, yielding similar KB estimates as for SK&F 97541. 6. It is concluded that at both the presynaptic and postsynaptic sites examined, SK&F 97541 was about 10 fold more potent than baclofen or 3-APPA. The antagonists CGP 35348 and 3-APHPA (KB 1O-20 microM) were about 20 fold more potent than phaclofen. The similarities in relative agonist potency and estimated antagonist affinity between these two functionally distinct GABAB receptors renders them pharmacologically indistinguishable at present.