Design and Development of Novel Barbiturates of Pharmacological Interest

Abstract ID 24095 Poster Board 366 GABA(A) receptors are ubiquitous in the CNS system where they mediate inhibitory synaptic signaling. These channels are targets of many pharmacological agents such as general anesthetics, sedatives, anticonvulsants, anxiolytics and anti-epileptics. GABA(A)Rs function is modulated by positive, negative and null allosteric modulators/ligands (PAMs, NAMs and NALs) that bind in the interfaces between the subunits. It is intuitive that these allosteric ligands influence the conformational stability and consequently the kinetic equilibria of different states of the channel during gating. Our goal is to design and develop NALs for GABA(A)Rs as reversal agents for general anesthesia and potentially non-sedative antiepileptics. These agents would attenuate the postoperative anesthesia-related complications such as, memory loss and confusion, by expediting the recovery from general anesthesia. The only clinically used NAL, flumazenil, binds to the benzodiazepine (BDZ) site in the extracellular domain's (ECD) α+/γ- interface, and is an antagonists of benzodiazepine sedatives. We embarked on a drug design campaign based on the structures of etomidate, flavanols and barbiturates, ligands that bind in the transmembrane domain sites (TMD). In the design and discovery of the new molecules, we used computational docking, structure-activity relationship studies and radioligand binding assays. We found that novel spiro-barbiturates analogs of phenobarbital bind to the GABA(A)Rs and reverse the R-mTFD-MPAB-induced anesthesia, while having only a marginal effect on agonist, [³H]muscimol, binding. The SAR study guided by the radioligand binding assays and the in vivo experiments of these novel barbiturates will be presented. The discovery of the first NALs that reverse anesthesia induced by positive allosteric modulators (PAMs) of GABA(A)Rs bound to the TMD will help understand GABAergic actions in the CNS, and potentially lead to antidotes for general anesthesia and other GABAergic CNS drugs. Support/Funding Information: National Institute for General Medical Sciences, R01 GM135550