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

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

SN - 0022-2623

VL - 40

SP - 1668

EP - 1681

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 11

ER -