CHEMISTRY, BINDING AFFINITIES, AND BEHAVIORAL PROPERTIES OF A NEW CLASS OF ANTINEOPHOBIC MITOCHONDRIAL DBI RECEPTOR COMPLEX (MDRC) LIGANDS

The mitochondrial DBI receptor complex (mDRC; previously called the pe ripheral benzodiazepine receptors) is linked to the production of neur osteroids such as pregnenolone sulfate, dehydroepiandrosterone sulfate , and others. In order to gain further information as to the function of the mDRC in the brain, we have constructed and tested both in vitro and in vivo a novel series of ligands, 2-arylindole-3-acetamides. The SAR studies detailed herein delineate some of the structural features required for high affinity binding to the mDRCs. In most cases the ne w ligands were prepared by use of the Fischer indole synthesis. Variat ions in the length and number of the alkyl groups on the amide nitroge n were probed together with the effects of halogen substituents on one or both of the aryl rings. Some ligands were also synthesized for stu dy which represent conformationally constrained versions of the parent structure. Broad screening studies revealed these indoleacetamides to be highly selective for the mDRC, since they failed to bind with any significant affinity to other receptor systems. Some of the ligands we re found to exhibit K(i) values in the low nanomolar range for the mDR C as measured by the displacement of [H-3]4'-chlorodiazepam. A subset of these ligands was also shown to stimulate pregnenolone formation fr om the mitochondria of C6-2B glioma cells with an EC50 of about 3 nM. In animal experiments ligands selected for further study were found to exhibit antineophobic effects, in spite of the fact that they exhibit no direct action on GABA(A) receptors. Consequently, it is postulated that these ligands owe their action to an indirect modulation of GABA (A) receptor function, presumably by stimulation of neurosteroid produ ction and release from glial cells, followed by neurosteroid modulatio n of GABA's action on the chloride ion channel conductance of GABA(A) receptors.