Theresa M. Schwartz

Synthesis and pharmacological evaluation of sulfone substituted HIV protease inhibitors

Abstract The sulfonamide substituted pyranones ( 1 ) have recently been shown to be potent HIV protease inhibitors. We prepared a series of sulfone substituted analogs and compared their biological activities to those of the corresponding sulfonamide analogs. It was determined that although these compounds maintained activity as enzyme inhibitors, they showed somewhat diminished antiviral activity even though they may possess increased membrane permeability.

PNU-107484A with α isoform-dependent functional changes in αxβ2γ2 subtypes of rat recombinant GABAA receptors

1 We discovered a novel γ‐aminobutyric acidA (GABAA) receptor ligand displaying seemingly opposite functionalities, depending on the α isoform of the αxβ2γ2 subtypes. PNU‐107484A enhanced GABA‐induced Cl− currents in the α1β2γ2 subtype, but inhibited the currents in the α3β2γ2 and α6β2γ2 subtypes, and its half‐maximal concentrations in the subtypes were 3.1±0.5, 4.2±1, and 3.5±0.2 μM, respectively, without showing much dependency on α isoforms. 2 In the α1β2 subtype, the drug at concentrations up to 40 μM showed no effect on GABA‐induced Cl− currents, suggesting the requirement of the γ subunit for its action. 3 PNU‐107484A behaved like a positive allosteric modulator of the α1β2γ2 subtype with its binding site distinct from those for benzodiazepines, barbiturates and neurosteroids. With the α3β2γ2 subtype, the drug behaved like a non‐competitive inhibitor of GABA, thus blocking Cl− currents by GABA alone or in the presence of pentobarbitone and neurosteroids. 4 It appears that PNU‐107484A is a unique GABAA receptor ligand with α isoform‐dependent functionalities, which may provide a basis for development of α isoform‐selective ligands, and it could be useful as a probe to investigate the physiological roles of the various α isoform subtypes.

PNU-107484A with alpha isoform-dependent functional changes in alpha(x)beta2gamma2 subtypes of rat recombinant GABA(A) receptors.

1 We discovered a novel γ‐aminobutyric acidA (GABAA) receptor ligand displaying seemingly opposite functionalities, depending on the α isoform of the αxβ2γ2 subtypes. PNU‐107484A enhanced GABA‐induced Cl− currents in the α1β2γ2 subtype, but inhibited the currents in the α3β2γ2 and α6β2γ2 subtypes, and its half‐maximal concentrations in the subtypes were 3.1±0.5, 4.2±1, and 3.5±0.2 μM, respectively, without showing much dependency on α isoforms. 2 In the α1β2 subtype, the drug at concentrations up to 40 μM showed no effect on GABA‐induced Cl− currents, suggesting the requirement of the γ subunit for its action. 3 PNU‐107484A behaved like a positive allosteric modulator of the α1β2γ2 subtype with its binding site distinct from those for benzodiazepines, barbiturates and neurosteroids. With the α3β2γ2 subtype, the drug behaved like a non‐competitive inhibitor of GABA, thus blocking Cl− currents by GABA alone or in the presence of pentobarbitone and neurosteroids. 4 It appears that PNU‐107484A is a unique GABAA receptor ligand with α isoform‐dependent functionalities, which may provide a basis for development of α isoform‐selective ligands, and it could be useful as a probe to investigate the physiological roles of the various α isoform subtypes.

PNU-107484A withαisoform-dependent functional changes inαxβ2γ2 subtypes of rat recombinant GABAAreceptors

1 We discovered a novel γ‐aminobutyric acidA (GABAA) receptor ligand displaying seemingly opposite functionalities, depending on the α isoform of the αxβ2γ2 subtypes. PNU‐107484A enhanced GABA‐induced Cl− currents in the α1β2γ2 subtype, but inhibited the currents in the α3β2γ2 and α6β2γ2 subtypes, and its half‐maximal concentrations in the subtypes were 3.1±0.5, 4.2±1, and 3.5±0.2 μM, respectively, without showing much dependency on α isoforms. 2 In the α1β2 subtype, the drug at concentrations up to 40 μM showed no effect on GABA‐induced Cl− currents, suggesting the requirement of the γ subunit for its action. 3 PNU‐107484A behaved like a positive allosteric modulator of the α1β2γ2 subtype with its binding site distinct from those for benzodiazepines, barbiturates and neurosteroids. With the α3β2γ2 subtype, the drug behaved like a non‐competitive inhibitor of GABA, thus blocking Cl− currents by GABA alone or in the presence of pentobarbitone and neurosteroids. 4 It appears that PNU‐107484A is a unique GABAA receptor ligand with α isoform‐dependent functionalities, which may provide a basis for development of α isoform‐selective ligands, and it could be useful as a probe to investigate the physiological roles of the various α isoform subtypes.