Phosphorus analogs of .gamma.-aminobutyric acid, a new class of anticonvulsants

Cates, Lindley A.; Li, Ven Shun; Yakshe, Chriss C.; Fadeyi, Michael; Andree, Terrance H.; Karbon, E.W.; Enna, S.J.

doi:10.1021/jm00371a017

Cited by 15 publications

(7 citation statements)

References 8 publications

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“…O-Demethylation using Li(s-Bu) 3 BH, as described in Chowdhury et al (2007), followed by hydrogenolytic removal of the Cbz group, afforded the products in 73% [(R)-11] or 60% [(S)-11] yield over the three steps. Finally, 2-aminoethyl benzylphosphonate (12) was synthesized in 55% yield in a single step by reaction of benzylphosphonic acid with aziridine using an adaptation of the procedure described by Cates et al (1984) for preparation of 2-aminoethyl phenylphosphonate (Fig. 2D).…”

Section: Resultsmentioning

confidence: 99%

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2-Aminoethyl Methylphosphonate, a Potent and Rapidly Acting Antagonist of GABA_A-ρ1 Receptors

Xie¹,

Yan²,

Lan³

et al. 2011

Mol Pharmacol

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2-Aminoethyl methylphosphonate (2-AEMP), an analog of GABA, has been found to exhibit antagonist activity at GABA A -1 (also known as 1 GABA C ) receptors. The present study was undertaken to elucidate 2-AEMP's action and to test the activities of 2-AEMP analogs. Whole-cell patch-clamp techniques were used to record membrane currents in neuroblastoma cells stably transfected with human GABA A -1 receptors. The action of 2-AEMP was compared with that of 1,2,5,6-tetrahydropyridin-4-yl methylphosphinic acid (TPMPA), a commonly used GABA A -1 antagonist. With 10 M GABA, 2-AEMP's IC 50 (18 M) differed by less than 2.5-fold from that of TPMPA (7 M), and results obtained were consistent with a primarily competitive mode of inhibition by 2-AEMP. Terminating the presentation of 2-AEMP or TPMPA in the presence of GABA produced a release from inhibition. However, the rate of inhibition release upon the termination of 2-AEMP considerably exceeded that determined with termination of TPMPA. Moreover, when presented at concentrations near their respective IC 50 values, the preincubation period associated with 2-AEMP's onset of inhibition was much shorter than that for TPMPA. Analogs of 2-AEMP possessing a benzyl or n-butyl rather than a methyl substituent at the phosphorus atom, as well as analogs bearing a C-methyl substituent on the aminoethyl side chain, exhibited reduced potency relative to 2-AEMP. Of these analogs, only (R)-2-aminopropyl methylphosphonate significantly diminished the response to 10 M GABA. Structure-activity relationships are discussed in the context of molecular modeling of ligand binding to the antagonist binding site of the GABA A -1 receptor.

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Section: Resultsmentioning

confidence: 99%

“…Cates et al (1984) showed that 2-aminoethyl phenylphosphonate weakly inhibits the binding of [ 3 H]GABA to GABA A and GABA B receptors in rat brain. Overall however, phosphonic analogs of GABA are much less well characterized, and structure-activity relationships within this class are unknown.…”

Section: Gaba (mentioning

confidence: 99%

2-Aminoethyl Methylphosphonate, a Potent and Rapidly Acting Antagonist of GABA_A-ρ1 Receptors

Xie¹,

Yan²,

Lan³

et al. 2011

Mol Pharmacol

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“…TPMPA, which is a weaker GABA B agonist than 3-APMPA (Ragozzino et al 1996), had an intermediate effect on the nSTR. Thus, the cyclic tetrahydropyridyl side chain of TPMPA may be needed to attenuate the GABA B R agonism of 3-APMPA, whereas the 2-aminoethoxy side chain of 2- AEMP, which is isosteric to the side chain of 3-APMPA, appears to convey intrinsically weak agonism at GABA B R. Because to date only a few 2-aminoethyl phosphonates have been tested for interaction with GABA receptors (Cates et al 1984; Chowdhury et al 2007; Xie et al 2011), and none have been specifically tested at GABA B R, conclusive testing of the structure-activity properties just noted will require further investigations. Overall, the present and previous evidence for 2-AEMP’s selectivity for GABA C R, together with its ease of synthesis, emphasize the desirability of its further study in the field of GABA C R pharmacology.…”

Section: Discussionmentioning

confidence: 99%

“…Retinal GABA A receptors are less sensitive and are more rapidly desensitized than GABA C R (Cates et al 1984; Eggers and Lukasiewicz 2011; Lukasiewicz and Shields 1998). Activation of retinal GABA A R is likely to have an inhibitory effect on bipolar cell responses, and these receptors likely do not mediate the tonic effects on membrane potential that have been ascribed to GABA C R in the retina.…”

Section: Discussionmentioning

confidence: 99%

In vivo electroretinographic studies of the role of GABAC receptors in retinal signal processing

Wang

Mojumder

Yan

et al. 2015

Experimental Eye Research

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All three classes of receptors for the inhibitory neurotransmitter GABA (GABAR) are expressed in the retina. This study investigated roles of GABAR, especially GABACR (GABA(A)-ρ), in retinal signaling in vivo by studying effects on the mouse electroretinogram (ERG) of genetic deletion of GABACR versus pharmacological blockade using receptor antagonists. Brief full-field flash ERGs were recorded from anesthetized GABACR−/− mice, and WT C57BL/6 (B6) mice, before and after intravitreal injection of GABACR antagonists, TPMPA, 3-APMPA, or the more recently developed 2-AEMP; GABAAR antagonist, SR95531; GABABR antagonist, CGP, and agonist, baclofen. Intravitreal injections of TPMPA and SR95531 were also made in Brown Norway rats. The effect of 2-AEMP on GABA- induced current was tested directly in isolated rat rod bipolar cells, and 2-AEMP was found to preferentially block GABACR in those cells. Maximum amplitudes of dark (DA) and light-adapted (LA) ERG b-waves were reduced in GABACR−/− mice, compared to B6 mice, by 30–60%; a-waves were unaltered and oscillatory potential amplitudes were increased. In B6 mice, after injection of TPMPA (also in rats), 3-APMPA or 2-AEMP, ERGs became similar to ERGs of GABACR−/− mice. Blockade of GABAARs and GABABRs, or agonism of GABABRs did not alter B6 DA b-wave amplitude. The negative scotopic threshold response (nSTR) was slightly less sensitive in GABACR−/− than in B6 mice, and unaltered by 2-AEMP. However, amplitudes of nSTR and photopic negative response (PhNR), both of which originate from inner retina, were enhanced by TPMPA and 3-APMPA, each of which has GABAB agonist properties, and further increased by baclofen. The finding that genetic deletion of GABACR, the GABACR antagonist 2-AEMP, and other antagonists all reduced ERG b-wave amplitude, supports a role for GABACR in determining the maximum response amplitude of bipolar cells contributing to the b-wave. GABACR antagonists differed in their effects on nSTR and PhNR; antagonists with GABAB agonist properties enhanced light-driven responses whereas 2-AEMP did not.

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“…As a background to the development of phaclofen, we examined the actions of a number of phosphono-analogues of GABA at GABAB-receptors, there being two considerations that prompted our search for antagonists amongst such phosphono-analogues. Firstly, although previously found inactive in the periphery (Muhyaddin et al, 1982), 3-APPA depresses central neuronal activity in a bicuculline-insensitive manner (Curtis & Watkins, 1965;Bioulac et al, 1979), and shows affinity for GABA5-receptors (Cates et al, 1984) suggesting that 3-APPA might be a GABA.-receptor agonist; preliminary investigations showed 3-APPA in fact to be a partial agonist at these receptors ; see also Luzzi et al, 1986 which appeared contemporaneously). Secondly, antagonism is conferred upon glutamate analogues by co-phosphono-substitution (Watkins, 1981), which in turn originally suggested to us that similar analogues of GABA might be antagonists at GABA3-receptors.…”

Section: Introductionmentioning

confidence: 94%

Antagonism of GABA_B‐receptor‐mediated responses in the guinea‐pig isolated ileum and vas deferens by phosphono‐analogues of GABA

Kerr

Ong

Prager

1990

British J Pharmacology

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1 The phosphono-analogues of y-aminobutyric acid (GABA), 4-amino-butylphosphonic acid (4-ABPA), 3-amino-2(4-chlorophenyl)-propylphosphonic acid (phaclofen) and 3-amino-2-cyclohexylpropylphosphonic acid, each antagonized the GABA-and baclofen-induced GABAB-receptor-mediated depression of twitch responses to transmural stimulation in the guinea-pig isolated ileum, in a concentration-dependent, reversible and surmountable manner (apparent pA2 = 4.0 + 0.1, 4 + 0.2 and 3.7 + 0.2 respectively, compared with 3.9 + 0.1 for 6-aminovaleric acid). No such activity was found in a variety of related analogues. 2 By contrast, 3-amino-propylphosphonic acid (3-APPA) behaved as a partial agonist, itself partly depressing ileal twitch contractions in a manner sensitive to 4-ABPA and phaclofen, as well as antagonizing the depression of the ileal twitch by GABA and baclofen (apparent pA2 = 4.0 + 0.2). 3 Both 4-ABPA and phaclofen also antagonized the baclofen-induced depression of the twitch in the guinea-pig isolated vas deferens (apparent pA2 = 4.0 ± 0.1 for each), whilst 3-APPA behaved as a partial agonist, slightly depressing the vas twitch, and antagonised the baclofen-induced depression of the twitch (apparent pA2 = 3.9 + 0.1). 4 None of these phosphono-analogues exhibited any action at ileal GABAA-receptors, nor influenced the ileal twitch depression with morphine, adenosine or noradrenaline, suggesting their selectivity as antagonists at GABAB-receptors.

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Phosphorus analogs of .gamma.-aminobutyric acid, a new class of anticonvulsants

Cited by 15 publications

References 8 publications

2-Aminoethyl Methylphosphonate, a Potent and Rapidly Acting Antagonist of GABA_A-ρ1 Receptors

2-Aminoethyl Methylphosphonate, a Potent and Rapidly Acting Antagonist of GABA_A-ρ1 Receptors

In vivo electroretinographic studies of the role of GABAC receptors in retinal signal processing

Antagonism of GABA_B‐receptor‐mediated responses in the guinea‐pig isolated ileum and vas deferens by phosphono‐analogues of GABA

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Phosphorus analogs of .gamma.-aminobutyric acid, a new class of anticonvulsants

Cited by 15 publications

References 8 publications

2-Aminoethyl Methylphosphonate, a Potent and Rapidly Acting Antagonist of GABAA-ρ1 Receptors

2-Aminoethyl Methylphosphonate, a Potent and Rapidly Acting Antagonist of GABAA-ρ1 Receptors

In vivo electroretinographic studies of the role of GABAC receptors in retinal signal processing

Antagonism of GABAB‐receptor‐mediated responses in the guinea‐pig isolated ileum and vas deferens by phosphono‐analogues of GABA

Contact Info

Product

Resources

About

2-Aminoethyl Methylphosphonate, a Potent and Rapidly Acting Antagonist of GABA_A-ρ1 Receptors

2-Aminoethyl Methylphosphonate, a Potent and Rapidly Acting Antagonist of GABA_A-ρ1 Receptors

Antagonism of GABA_B‐receptor‐mediated responses in the guinea‐pig isolated ileum and vas deferens by phosphono‐analogues of GABA