Linked Life Data

15687371

Source:http://linkedlifedata.com/resource/pubmed/id/15687371

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2005-5-18
pubmed:abstractText
Benzodiazepines (BZs) are prescribed for a variety of disorders, including those involving anxiety and sleep, but have unwanted side effects that limit their use. Elucidating the GABA(A) receptor mechanisms underlying the behavioral effects of BZs will help develop new drugs having both maximum clinical benefit and minimum adverse side effects. A recently developed compound is SL651498 [6-fluoro-9-methyl-2-phenyl-4-(pyrrolidin-1-yl-carbonyl)-2,9-dihydro-1H-pyridol[3,4-b]indol-1-one], which is a full agonist at GABA(A) receptors containing alpha(2)and alpha(3) subunits and a partial agonist at GABA(A) receptors containing alpha(1) and alpha(5) subunits. We assessed the ability of SL651498 to engender anxiolytic-like, motor, and subjective effects characteristic of BZ-type drugs in nonhuman primates. Anxiolytic-like activity was assessed with a conflict procedure in rhesus monkeys. Motor effects were evaluated in squirrel monkeys using observational techniques, and the subjective effects of SL651498 were assessed in squirrel monkeys trained to discriminate the nonselective BZ triazolam from saline. SL651498 engendered anxiolytic-like effects similar to conventional BZs. In addition, SL651498 fully induced muscle relaxation, but unlike conventional BZs, engendered minimal ataxia. In drug discrimination studies, SL651498 partially substituted for triazolam. This effect was blocked with the alpha(1) GABA(A) subtype-preferring antagonist beta-CCT (beta-carboline-3-carboxylate-t-butyl ester), implicating alpha(1) GABA(A) effects receptors in the subjective of SL651498. Together, these studies suggest that compounds such as SL651498 that have high intrinsic efficacy at alpha(2)GABA(A) and/or alpha(3)GABA(A) receptors may have clinical potential as anxiolytics and muscle relaxants. Moreover, a compound with reduced efficacy at alpha(1) GABA(A) and/or alpha(5) GABA(A) receptors may lack some of the motor and subjective effects associated with conventional BZs.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0022-3565
pubmed:author
pubmed:issnType
Print
pubmed:volume
313
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1118-25
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
2005
pubmed:articleTitle
Contribution of GABAA receptor subtypes to the anxiolytic-like, motor, and discriminative stimulus effects of benzodiazepines: studies with the functionally selective ligand SL651498 [6-fluoro-9-methyl-2-phenyl-4-(pyrrolidin-1-yl-carbonyl)-2,9-dihydro-1H-pyridol[3,4-b]indol-1-one].
pubmed:affiliation
Harvard Medical School, New England Primate Research Center, Southborough, MA 01772, USA. stephanie_licata@hms.harvard.edu
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, N.I.H., Extramural