Conserved site for neurosteroid modulation of GABAA receptors

Hosie, Alastair M.; Clarke, Laura; Silva, Helena da; Smart, Trevor G.

doi:10.1016/j.neuropharm.2008.07.050

Cited by 155 publications

(167 citation statements)

References 42 publications

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“…This strategy has already proved instructive in accelerating the identification of drug targets. For example, the hitherto elusive steroid site on the GABA receptor was identified in a comprehensive comparison between Drosophila melanogaster GABA-gated chloride channels and human GABA A type receptors [16]. We have previously shown that the anthelmintic compound, IVM, enhanced ACh-induced 7 amplitude responses, confirming the earlier finding of Bertrand and colleagues [17], while slightly attenuating responses of ACR-16 [18] , a Caenorhabditis elegans α7 homologue [19,20].…”

Section: Page 4 Of 26supporting

confidence: 76%

“…These molecules include anaesthetics [28,29], alcohols [30], endogenous neurosteroids [16] and androgenic steroids [31] (Fig. 5).…”

Section: Page 11 Of 26mentioning

confidence: 99%

“…Three residues in TM1-3, which have been well-characterised in GABA receptors, form a binding pocket with which general anaesthetics can interact [16,28]. Residues in TM1 and TM4 play a major role in the binding of neurosteroids.…”

Section: Page 11 Of 26mentioning

confidence: 99%

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Comparative pharmacology and computational modelling yield insights into allosteric modulation of human α7 nicotinic acetylcholine receptors

Sattelle

Akamatsu²,

Matsuda³

et al. 2009

Biochemical Pharmacology

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HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Section: Page 4 Of 26supporting

confidence: 76%

“…These molecules include anaesthetics [28,29], alcohols [30], endogenous neurosteroids [16] and androgenic steroids [31] (Fig. 5).…”

Section: Page 11 Of 26mentioning

confidence: 99%

See 1 more Smart Citation

Comparative pharmacology and computational modelling yield insights into allosteric modulation of human α7 nicotinic acetylcholine receptors

Sattelle

Akamatsu²,

Matsuda³

et al. 2009

Biochemical Pharmacology

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“…The compounds from the 5-series 1a, 3, 12, 13, 15, 24, 39, 44, 45, 47, 48, 49, 56 and 59 were chosen as training-set to develop the 3D-QSAR models. Compound 19 was excluded from this study since it was only tested at concentrations up to 100 μM and its EC 50 could not be determined. Compounds 24, 39 and 49 were arbitrarily assigned an EC 50 value of 1 mM (other values were tried up to 10 mM that yielded similar results) based on the experimentally determined low limit (>300 μM) for their real EC 50 .…”

Section: Methodsmentioning

confidence: 99%

“…50 Similarly, a second binding site that spans the α,β-subunit interface, implying residues αT236 and βY284, and which is exclusively involved in direct receptor activation, was also identified. The existence of additional sites that mediate the action of neurosteroids is still a matter of debate.…”

Section: D-qsar Analysismentioning

confidence: 97%

Allopregnanolone and Pregnanolone Analogues Modified in the C Ring: Synthesis and Activity

et al. 2013

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Abstract(25R)-3β-Hydroxy-5α-spirostan-12-one (hecogenin) and 11α-hydroxypregn-4-ene-3,20-dione (11α-hydroxyprogesterone) were used as starting materials for the synthesis of a series of 11-and 12-substituted derivatives of 5ξ-pregnanolone (3α-hydroxy-5α-pregnan-20-one and 3α-hydroxy-5-pregnan-20-one), the principal neurosteroid acting via γ-aminobutyric acid (GABA). These analogues were designed to study the structural requirements of the corresponding GABA A receptor. Their biological activity was measured by in vitro test with groups at the C-ring edge, rather than on specific interactions between them and the receptor.3 IntroductionAlthough steroids in general are widely understood as a class of natural products, which hold only little potential of a new breakthrough, neurosteroids are still studied with great interest (see the "Neurosteroid" copy 1,2 of Pharmacol. Ther. 2007 or recent papers [3][4][5][6] ). Unlike the family of other steroid hormones, neurosteroids do not bind to nuclear but to membrane receptors for neurotransmitters. One of the neurotransmitters -γ-aminobutyric acid (GABA) elicits the influx of chloride ions into neuronal cells, which changes the membrane potential of a given cell, which in turn prevents the transmission of subsequent neuronal signals.In agreement with this action, neurosteroids such as allopregnanolone or pregnanolone (1a and 1b, respectively, see Figure 1), 3α,5α-tetrahydrodeoxycorticosterone (2), and some of their analogues, acting via the GABA A receptor, have anxiolytic, anaesthetic, anticonvulsant, and sedative properties. 7,8 Many new types of such analogues were prepared in order to refine the knowledge of relationship between the structure of compounds and their neuronal activity.These analogues either involve compounds with additional substituents (eg., alphaxalone, 3), or have their skeleton modified by increasing 9 or decreasing 10-12 the flexibility of the molecule or even reversing its chirality. 13 Various changes were also made to the steroid side chain. [14][15][16][17] Even heteroatoms (O, N, S) were introduced into the steroid framework with varied success. 18-21Almost all the active analogues contained a hydroxyl group in position 3α. Its presence has been considered essential for the activity, even though a 3α-amino analogue, lacking the 3α-hydroxyl (i. e., 4) retained 56% of the activity of allopregnanolone. 22In our search for new analogues of allopreganolone, we prepared a number of 5-pregnane derivatives designed to exert a higher solubility in water than the principal neurosteroid 1a.The biological activity of the new products was assessed using in vitro tests, which measured 4 the binding of labelled ligands to GABA A receptors in the absence and presence of the tested compounds. In our previous paper we reported structure modification of the steroidal B ring. 11Some anomalies in the structure of the analogues were tolerated by the GABA A receptor, others not; the biological consequences of the structure modification were rationalized using...

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Neurosteroid Influences on Neuronal Excitability

Reddy

2013

Epilepsy in Women

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Conserved site for neurosteroid modulation of GABAA receptors

Cited by 155 publications

References 42 publications

Comparative pharmacology and computational modelling yield insights into allosteric modulation of human α7 nicotinic acetylcholine receptors

Comparative pharmacology and computational modelling yield insights into allosteric modulation of human α7 nicotinic acetylcholine receptors

Allopregnanolone and Pregnanolone Analogues Modified in the C Ring: Synthesis and Activity

Neurosteroid Influences on Neuronal Excitability

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