Method, compositions, and compounds for modulating brain excitability
AssigneeUniversity of Southern California
InventorsKelvin W. Gee, Michael B. Bolger, Roberta E. Brinton, Deborah J. Burke, Bruce S. McEwen
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Abstract
Method, compositions, and compounds for modulating brain excitability to alleviate stress, anxiety, and seizure activity using certain steroid derivatives that act at a newly identified site on the gamma-ammobutyric acid/benzodiazepine receptor-chloride ionophore (GBR) complex.
Claims12
A method for modulating the excitability of the central nervous system as mediated by the ability to regulate chloride ion channels associated with the GABA-benzodiazepine receptor complex comprising administering to a patient in need of such treatment a central nervous system excitability modulating pharmaceutically effective amount of a 3-hydroxylated-5-reduced neuroactive steriod compound that activates the GABA-benzodiazepine receptor-chloride ionopore complex by attaching to a brain receptor site other than any previously known recognition site of said complex, but associated with and still activating said complex.
A compound of the formula:
- ##STR35## wherein R1 is selected from the group consisting of hydroxy, ##STR36## wherein R6, R7 and R8 are individually a C.sub.1 -C.sub.20 straight chain aliphatic radical, C.sub.1 -C.sub.20 branched chain aliphatic radical or C.sub.3 -C.sub.20 cyclic aliphatic radical, or aromatic radical, or a heterocyclic radical selected from the group consisting of 1-methyl-1,4-dihydronicotinoyl, piperidinyl, pyridinyl, furanyl, thiophenyl, and pyrazinyl, and Y is --O-- or --S--;
- R2 is selected from the group consisting of ##STR37## wherein R9, R10, R11, R12, R13, R14, R17, R18, R19 and R20 are individually a C.sub.1 -C.sub.20 straight chain aliphatic radical, C.sub.1 -C.sub.20 branched chain aliphatic radical or C.sub.3 -C.sub.20 cyclic aliphatic radical, or aromatic radical, or a heterocyclic radical selected from the group consisting of 1-methyl-1,4-dihydronicotinoyl, piperidinyl, pyridinyl, furanyl, thiophenyl, and pyrazinyl with the provisos that
- (1) R9, R10 and R11 may also individually be an amide ##STR38## radical wherein R15 and R16 individually are a C.sub.1 -C.sub.20 straight chain aliphatic radical, C.sub.1 -C.sub.20 branched chain aliphatic radical or C.sub.3 -C.sub.20 cyclic aliphatic radical, or aromatic radical, or a heterocyclic radical selected from the group consisting of 1-methyl-1,4-dihydronicotinoyl, piperidinyl, pyridinyl, furanyl, thiophenyl, and pyrazinyl, and n=1 to 8 and
- (2) R19 and R20 may also individually be H or ##STR39## wherein R21 is H or a C.sub.1 -C.sub.20 straight chain aliphatic radical, C.sub.1 -C.sub.20 branched chain aliphatic radical or C.sub.3 -C.sub.20 cyclic aliphatic radical, or aromatic radical, or a heterocyclic radical selected from the group consisting ob 1-methyl-1,4-dihydronicotinoyl, piperidinyl, pyridinyl, furanyl, thiophenyl, and pyrazinyl, and n is an integer of 1 to 8;
- R3 is selected from the group consisting of hydrogen, hydroxy, keto, C.sub.1 -C.sub.18 alkyloxy, aryloxy and amino;
- and
- R4 and R5 individually are selected from the group consisting of C.sub.1 -C.sub.18 alkyl, aryl, halo and trifluoroalkyl.
Dependencies are inferred from the claim text.