Synthesis of γ-Aminopropylphosphonous Acids Using Hypophosphorous Acid Synthons

Dinawall, J. G.; Ehrenfreund, Josef; Hall, Roger G.; Jack, J.

doi:10.1080/03086648708079129

Cited by 33 publications

(11 citation statements)

References 3 publications

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“…This agonist belongs to the group of y-aminopropyl-phosphonous acids, which bind with a high specificity to GABAB receptors of vertebrate CNS [27]. It has been recently reported that this agonist inhibits the heart beat of the marine arachnid Limulus polyphemus, but fails to activate the locust thoracic soma1 GABA receptors [ 161.…”

Section: Gaba Receptor Multiplicitymentioning

confidence: 99%

Functional assay for GABA receptor subtypes of a cockroach giant interneuron

Hue¹

1991

Arch Insect Biochem Physiol

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gamma-Aminobutyric acid (GABA) receptors were examined in the cockroach central nervous system (CNS) using the single fiber-oil gap method applied to an identified giant interneuron. Short-lasting pressure application of 10 mM GABA developed a multiphasic response composed of a fast hyperpolarization followed by a transient depolarizing component and a stable hyperpolarization. This triphasic characteristic shape of the response was modified according to the dose of GABA injected or bath-applied and to the precise localization of the injection within the dendritic area. The transient depolarizing phase showed a negative reversal potential of -70 mV. Both hyperpolarizing phases reversed at a more negative level ranging to -80 mV. A positive shift of these values was caused by a decrease in external chloride concentration. Bath-application of 0.1 mM picrotoxin (Ptx) decreased the depolarizing phase which was progressively replaced by a stable hyperpolarization. The transient depolarizing component desensitized quickly and was the most sensitive phase to Ptx action. The Ptx-resistant response reversed at a mean value of -100 mV close to the equilibrium potential for potassium ions (EK+), suggesting that it was generated by a K(+)-channel coupled receptor. Although baclofen was unable to mimic the Ptx-resistant GABA response, the compound CGA 147823, known to bind with a high specificity to vertebrate GABAB receptors, has been successfully used to reproduce the Ptx-resistant GABA response. It is suggested that, in addition to GABA receptors linked to chloride channels, the insect CNS possesses GABA receptors sharing ionic characteristics of GABAB receptors especially those located in the vertebrate CNS, although they are insensitive to baclofen.

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Section: Gaba Receptor Multiplicitymentioning

confidence: 99%

Functional assay for GABA receptor subtypes of a cockroach giant interneuron

Hue¹

1991

Arch Insect Biochem Physiol

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“…[3(R)-Amino-2(R,S)-hydroxybutyl)phosphinic Acid (21). A solution of 9.6 mmol of lithium diisopropylamide in dry THF was cooled to -78 °C under argon, and a solution of 1.7 g (8 mmol) of 1822 in 15 mL of dry THF was added over 2 min by syringe.…”

Section: (Fi)-(jv-tritylamino)propanalmentioning

confidence: 99%

“…Electrophysiological experiments demonstrated that (3-aminopropyl)ethylphosphinic acid 3 (Table 1) and homologous alkylphosphinic acids (R > C2H5) were GABAb antagonists, as is described in part 2 of this series. 20 Chemistry Dingwall et al 21,22 described an efficient synthetic route for the preparation of phosphinic acid analogues of (natural) -, ß-, and y-amino acids. Although the phosphinic acid analogue of GABA, 2, displayed a significantly higher affinity to GABAb receptors than "Reagents and conditions: (i) LDA, THF, -78 °C -room temperature, 24 h; (ii) 2 M HC1, reflux, 4 h; propylene oxide, EtOH, room temperature, 24 h. the endogenous neurotransmitter in vitro, it was of little therapeutic value, because it did not show the pronounced muscle relaxant effects of baclofen in vivo (Table 8).…”

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confidence: 99%

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Phosphinic Acid Analogs of GABA. 1. New Potent and Selective GABAB Agonists

Froestl

Mickel²,

Hall³

et al. 1995

J. Med. Chem.

192

115

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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.

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“…Ultimately, it was in the area of γ-amino phosphinic acids that the breakthrough came. The parent compound, 3-aminopropylphosphinic acid was prepared [16] using a building block described above. This compound binds selectively to the GABA-B receptor with an affinity (1 × 10 -9 M) higher than that of the natural inhibitory neurotransmitter.…”

Section: Bioisosteric Replacement Of Carboxylic Acidsmentioning

confidence: 99%