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Different in vitro and in vivo profiles of substituted 3-aminopropylphosphinate and 3-aminopropyl(methyl)phosphinate GABA(B) receptor agonists as inhibitors of transient lower oesophageal sphincter relaxation.

ABSTRACT: Gastro-oesophageal reflux is predominantly caused by transient lower oesophageal sphincter relaxation (TLOSR) and GABA(B) receptor stimulation inhibits TLOSR. Lesogaberan produces fewer CNS side effects than baclofen, which has been attributed to its affinity for the GABA transporter (GAT), the action of which limits stimulation of central GABA(B) receptors. To understand the structure-activity relationship for analogues of lesogaberan (3-aminopropylphosphinic acids), and corresponding 3-aminopropyl(methyl)phosphinic acids, we have compared representatives of these classes in different in vitro and in vivo models.The compounds were characterized in terms of GABA(B) agonism in vitro. Binding to GATs and cellular uptake was done using rat brain membranes and slices respectively. TLOSR was measured in dogs, and CNS side effects were evaluated as hypothermia in mice and rats.3-Aminopropylphosphinic acids inhibited TLOSR with a superior therapeutic index compared to 3-aminopropyl(methyl)phosphinic acids. This difference was most likely due to differential GAT-mediated uptake into brain cells of the former but not latter. In agreement, 3-aminopropyl(methyl)phosphinic acids were much more potent in producing hypothermia in rats even when administered i.c.v.An enhanced therapeutic window for 3-aminopropylphosphinic acids compared with 3-aminopropyl(methyl)phosphinic acids with respect to inhibition of TLOSR was observed and is probably mechanistically linked to neural cell uptake of the former but not latter group of compounds. These findings offer a platform for discovery of new GABA(B) receptor agonists for the treatment of reflux disease and other conditions where selective peripheral GABA(B) receptor agonism may afford therapeutic effects.

SUBMITTER: Lehmann A

PROVIDER: S-EPMC3372828 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Different in vitro and in vivo profiles of substituted 3-aminopropylphosphinate and 3-aminopropyl(methyl)phosphinate GABA(B) receptor agonists as inhibitors of transient lower oesophageal sphincter relaxation.

Lehmann A A Antonsson M M Aurell-Holmberg A A Blackshaw L A LA Brändén L L Elebring T T Jensen J J Kärrberg L L Mattsson J P JP Nilsson K K Oja S S SS Saransaari P P von Unge S S

British journal of pharmacology 20120301 6

<h4>Background and purpose</h4>Gastro-oesophageal reflux is predominantly caused by transient lower oesophageal sphincter relaxation (TLOSR) and GABA(B) receptor stimulation inhibits TLOSR. Lesogaberan produces fewer CNS side effects than baclofen, which has been attributed to its affinity for the GABA transporter (GAT), the action of which limits stimulation of central GABA(B) receptors. To understand the structure-activity relationship for analogues of lesogaberan (3-aminopropylphosphinic acid ...[more]

PMID: 21950457

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Project description:1. The effects of endothelin-1 (ET-1) on guinea-pig lower oesophageal sphincter (LOS) circular smooth muscle were investigated by using intracellular microelectrodes and isometric tension recording techniques. 2. ET-1 produced biphasic mechanical responses; an initial transient relaxation followed by a sustained contraction. The initial relaxation was not inhibited by either tetrodotoxin (TTX, 1 microM) or L-N(G)-nitroarginine (L-NOARG, 100 microM). The sustained contraction was greatly attenuated by nifedipine (1 microM). 3. ET-1 (1 - 30 nM) induced a concentration-dependent hyperpolarisation that was unaffected by TTX or L-NOARG. The ET(A) receptor antagonist, BQ123 (0.3 microM) abolished the ET-1-induced hyperpolarisation, whereas the ET(B) receptor antagonist, BQ788 (0.3 microM) had no detectable effect. Sarafotoxin S6c (10 nM) did not change the membrane potential. 4. The ET-1-induced hyperpolarisation was abolished by apamin (0.1 microM). Interestingly, apamin abolished the ET-1-induced transient relaxation but potentiated the sustained contraction. 5. In Ca(2+)-free Krebs solution, the ET-1-induced hyperpolarisation was greatly attenuated and returned to the control value when the tissue was reperfused with Krebs solution containing Ca(2+). The ET-1-induced hyperpolarisation was insensitive to nifedipine but was attenuated by SK&F 96365 (1 - [beta-[3-(4 - methoxy - phenyl)propoxy] - 4 - methoxyphenethyl] - 1H-imidazole hydrochloride, 50 microM), an inhibitor of receptor-mediated Ca(2+) entry. The residual component of the ET-1-induced hyperpolarisation was sensitive to thapsigargin (1 microM). 6. These results demonstrate that, in guinea-pig LOS circular smooth muscle, ET-1 hyperpolarizes the membrane by activating apamin-sensitive K(+) channels, mainly as a result of receptor-mediated Ca(2+) entry and partly by Ca(2+) release from intracellular stores. The hyperpolarisation triggers the initial transient relaxation, which acts to oppose the sustained contraction.

Dataset Information

Different in vitro and in vivo profiles of substituted 3-aminopropylphosphinate and 3-aminopropyl(methyl)phosphinate GABA(B) receptor agonists as inhibitors of transient lower oesophageal sphincter relaxation.

Publications

Different in vitro and in vivo profiles of substituted 3-aminopropylphosphinate and 3-aminopropyl(methyl)phosphinate GABA(B) receptor agonists as inhibitors of transient lower oesophageal sphincter relaxation.

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