Anesthetic activity of novel water-soluble 2β-morpholinyl steroids and their modulatory effects at GABA(A) receptors

Alison Anderson, Andrew C. Boyd, Alan Byford, Alexander C. Campbell, David K. Gemmell, Niall M. Hamilton, David R. Hill, Claire Hill-Venning, Jeremy J. Lambert, Maurice S. Maidment, Valerie May, Richard J. Marshall, John A. Peters, David C. Rees, Donald Stevenson, Hardy Sundaram

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Abstract

(3α,5α)-3-Hydroxypregnan-20-ones and (3α,5α)-3-hydroxypregnane- 11,20-diones bearing a 2β-morpholinyl substituent were synthesized, and the utility of these steroids as anesthetic agents was evaluated through determination of their potency and duration of hypnotic activity in mice after intravenous administration. Alkylation of the morpholinyl substituent or chlorination at C-21 afforded the novel amino steroids (2β,3α,5α)-3- hydroxy-2-(2,2-dimethyl-4-morpholinyl)-pregnane-11,20-dione (19) and (2β,3α,5α)-21-chloro-3-hydroxy-2-(4-morpholinyl)pregnan-20-one (37) that were more potent and advantageously produced shorter sleep times than related compounds which were previously reported. Furthermore, salts of these and other amino steroids generally retained good aqueous solubility. In a radioligand binding assay the compounds inhibited the specific binding of [35S]-tert-butyl bicyclophosphorothionate to rat whole brain membranes, and in an electrophysiological assay they potentiated GABA(A) receptor-mediated currents recorded from voltage-clamped bovine chromaffin cells. These in vitro results are consistent with the anesthetic activity of the amino steroids being related to their modulatory effects at GABA(A) receptors.

Original languageEnglish
Pages (from-to)1668-1681
Number of pages14
JournalJournal of Medicinal Chemistry
Volume40
Issue number11
DOIs
Publication statusPublished - 23 May 1997

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GABA-A Receptors
Anesthetics
Steroids
Water
Pregnanolone
Radioligand Assay
Chromaffin Cells
Halogenation
Alkylation
Hypnotics and Sedatives
Intravenous Administration
Solubility
Sleep
Salts
Membranes
Brain

Cite this

Anderson, A., Boyd, A. C., Byford, A., Campbell, A. C., Gemmell, D. K., Hamilton, N. M., ... Sundaram, H. (1997). Anesthetic activity of novel water-soluble 2β-morpholinyl steroids and their modulatory effects at GABA(A) receptors. Journal of Medicinal Chemistry, 40(11), 1668-1681. https://doi.org/10.1021/jm960733n
Anderson, Alison ; Boyd, Andrew C. ; Byford, Alan ; Campbell, Alexander C. ; Gemmell, David K. ; Hamilton, Niall M. ; Hill, David R. ; Hill-Venning, Claire ; Lambert, Jeremy J. ; Maidment, Maurice S. ; May, Valerie ; Marshall, Richard J. ; Peters, John A. ; Rees, David C. ; Stevenson, Donald ; Sundaram, Hardy. / Anesthetic activity of novel water-soluble 2β-morpholinyl steroids and their modulatory effects at GABA(A) receptors. In: Journal of Medicinal Chemistry. 1997 ; Vol. 40, No. 11. pp. 1668-1681.
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abstract = "(3α,5α)-3-Hydroxypregnan-20-ones and (3α,5α)-3-hydroxypregnane- 11,20-diones bearing a 2β-morpholinyl substituent were synthesized, and the utility of these steroids as anesthetic agents was evaluated through determination of their potency and duration of hypnotic activity in mice after intravenous administration. Alkylation of the morpholinyl substituent or chlorination at C-21 afforded the novel amino steroids (2β,3α,5α)-3- hydroxy-2-(2,2-dimethyl-4-morpholinyl)-pregnane-11,20-dione (19) and (2β,3α,5α)-21-chloro-3-hydroxy-2-(4-morpholinyl)pregnan-20-one (37) that were more potent and advantageously produced shorter sleep times than related compounds which were previously reported. Furthermore, salts of these and other amino steroids generally retained good aqueous solubility. In a radioligand binding assay the compounds inhibited the specific binding of [35S]-tert-butyl bicyclophosphorothionate to rat whole brain membranes, and in an electrophysiological assay they potentiated GABA(A) receptor-mediated currents recorded from voltage-clamped bovine chromaffin cells. These in vitro results are consistent with the anesthetic activity of the amino steroids being related to their modulatory effects at GABA(A) receptors.",
author = "Alison Anderson and Boyd, {Andrew C.} and Alan Byford and Campbell, {Alexander C.} and Gemmell, {David K.} and Hamilton, {Niall M.} and Hill, {David R.} and Claire Hill-Venning and Lambert, {Jeremy J.} and Maidment, {Maurice S.} and Valerie May and Marshall, {Richard J.} and Peters, {John A.} and Rees, {David C.} and Donald Stevenson and Hardy Sundaram",
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Anderson, A, Boyd, AC, Byford, A, Campbell, AC, Gemmell, DK, Hamilton, NM, Hill, DR, Hill-Venning, C, Lambert, JJ, Maidment, MS, May, V, Marshall, RJ, Peters, JA, Rees, DC, Stevenson, D & Sundaram, H 1997, 'Anesthetic activity of novel water-soluble 2β-morpholinyl steroids and their modulatory effects at GABA(A) receptors', Journal of Medicinal Chemistry, vol. 40, no. 11, pp. 1668-1681. https://doi.org/10.1021/jm960733n

Anesthetic activity of novel water-soluble 2β-morpholinyl steroids and their modulatory effects at GABA(A) receptors. / Anderson, Alison; Boyd, Andrew C.; Byford, Alan; Campbell, Alexander C.; Gemmell, David K.; Hamilton, Niall M.; Hill, David R.; Hill-Venning, Claire; Lambert, Jeremy J.; Maidment, Maurice S.; May, Valerie; Marshall, Richard J.; Peters, John A.; Rees, David C.; Stevenson, Donald; Sundaram, Hardy.

In: Journal of Medicinal Chemistry, Vol. 40, No. 11, 23.05.1997, p. 1668-1681.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Anesthetic activity of novel water-soluble 2β-morpholinyl steroids and their modulatory effects at GABA(A) receptors

AU - Anderson, Alison

AU - Boyd, Andrew C.

AU - Byford, Alan

AU - Campbell, Alexander C.

AU - Gemmell, David K.

AU - Hamilton, Niall M.

AU - Hill, David R.

AU - Hill-Venning, Claire

AU - Lambert, Jeremy J.

AU - Maidment, Maurice S.

AU - May, Valerie

AU - Marshall, Richard J.

AU - Peters, John A.

AU - Rees, David C.

AU - Stevenson, Donald

AU - Sundaram, Hardy

PY - 1997/5/23

Y1 - 1997/5/23

N2 - (3α,5α)-3-Hydroxypregnan-20-ones and (3α,5α)-3-hydroxypregnane- 11,20-diones bearing a 2β-morpholinyl substituent were synthesized, and the utility of these steroids as anesthetic agents was evaluated through determination of their potency and duration of hypnotic activity in mice after intravenous administration. Alkylation of the morpholinyl substituent or chlorination at C-21 afforded the novel amino steroids (2β,3α,5α)-3- hydroxy-2-(2,2-dimethyl-4-morpholinyl)-pregnane-11,20-dione (19) and (2β,3α,5α)-21-chloro-3-hydroxy-2-(4-morpholinyl)pregnan-20-one (37) that were more potent and advantageously produced shorter sleep times than related compounds which were previously reported. Furthermore, salts of these and other amino steroids generally retained good aqueous solubility. In a radioligand binding assay the compounds inhibited the specific binding of [35S]-tert-butyl bicyclophosphorothionate to rat whole brain membranes, and in an electrophysiological assay they potentiated GABA(A) receptor-mediated currents recorded from voltage-clamped bovine chromaffin cells. These in vitro results are consistent with the anesthetic activity of the amino steroids being related to their modulatory effects at GABA(A) receptors.

AB - (3α,5α)-3-Hydroxypregnan-20-ones and (3α,5α)-3-hydroxypregnane- 11,20-diones bearing a 2β-morpholinyl substituent were synthesized, and the utility of these steroids as anesthetic agents was evaluated through determination of their potency and duration of hypnotic activity in mice after intravenous administration. Alkylation of the morpholinyl substituent or chlorination at C-21 afforded the novel amino steroids (2β,3α,5α)-3- hydroxy-2-(2,2-dimethyl-4-morpholinyl)-pregnane-11,20-dione (19) and (2β,3α,5α)-21-chloro-3-hydroxy-2-(4-morpholinyl)pregnan-20-one (37) that were more potent and advantageously produced shorter sleep times than related compounds which were previously reported. Furthermore, salts of these and other amino steroids generally retained good aqueous solubility. In a radioligand binding assay the compounds inhibited the specific binding of [35S]-tert-butyl bicyclophosphorothionate to rat whole brain membranes, and in an electrophysiological assay they potentiated GABA(A) receptor-mediated currents recorded from voltage-clamped bovine chromaffin cells. These in vitro results are consistent with the anesthetic activity of the amino steroids being related to their modulatory effects at GABA(A) receptors.

U2 - 10.1021/jm960733n

DO - 10.1021/jm960733n

M3 - Article

C2 - 9171876

AN - SCOPUS:0030982180

VL - 40

SP - 1668

EP - 1681

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

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ER -