TY - JOUR
T1 - Neurosteroid analogues. 11. Alternative ring system scaffolds
T2 - γ-aminobutyric acid receptor modulation and anesthetic actions of benz[f]indenes
AU - Scaglione, Jamie B.
AU - Manion, Brad D.
AU - Benz, Ann
AU - Taylor, Amanda
AU - DeKoster, Gregory T.
AU - Rath, Nigam P.
AU - Evers, Alex S.
AU - Zorumski, Charles F.
AU - Mennerick, Steven
AU - Covey, Douglas F.
PY - 2006/7/27
Y1 - 2006/7/27
N2 - Benz[f]indenes are tricyclic compounds with a linear 6-6-5 fused carbocyclic ring system. When properly substituted, benz[f]indenes can satisfy the pharmacophore requirements of the critical hydrogen-bond donor and acceptor groups found in neuroactive steroids that modulate γ-aminobutyric acidA (GABAA) receptor function. Thus, the benz[f]indene ring system provides an opportunity to extend the previously well-studied GABAA receptor structure-activity relationships (SAR) of neuroactive steroids to a different ring system. Depending on whether the stereochemistry of the 6-6-5 ring fusions are trans-trans or cis-trans, either planar or nonplanar benz[f]indenes are obtained. We found that the planar trans-trans benz[f]indenes are active, but less active than the steroids they were designed to mimic, whereas the nonplanar cis-trans compounds have little, if any, activity. The results provide new insight into the importance of the steroid framework for the actions of neuroactive steroids at GABAA receptors.
AB - Benz[f]indenes are tricyclic compounds with a linear 6-6-5 fused carbocyclic ring system. When properly substituted, benz[f]indenes can satisfy the pharmacophore requirements of the critical hydrogen-bond donor and acceptor groups found in neuroactive steroids that modulate γ-aminobutyric acidA (GABAA) receptor function. Thus, the benz[f]indene ring system provides an opportunity to extend the previously well-studied GABAA receptor structure-activity relationships (SAR) of neuroactive steroids to a different ring system. Depending on whether the stereochemistry of the 6-6-5 ring fusions are trans-trans or cis-trans, either planar or nonplanar benz[f]indenes are obtained. We found that the planar trans-trans benz[f]indenes are active, but less active than the steroids they were designed to mimic, whereas the nonplanar cis-trans compounds have little, if any, activity. The results provide new insight into the importance of the steroid framework for the actions of neuroactive steroids at GABAA receptors.
UR - http://www.scopus.com/inward/record.url?scp=33746665266&partnerID=8YFLogxK
U2 - 10.1021/jm0602920
DO - 10.1021/jm0602920
M3 - Article
C2 - 16854065
AN - SCOPUS:33746665266
SN - 0022-2623
VL - 49
SP - 4595
EP - 4605
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 15
ER -