Throughout history pathological or excessive anxiety has been clearly designated as undesirable and the understanding of its origin and treatment are a major concern. The benzodiazepines (Bz) employed to treat anxiety are a group of compounds with wide therapeutic applications as anxiolytics, anticonvulsants, hypnotics and muscle relaxants. These agents are now felt to exert their physiological effects via the GABA/Bz/C1 complex. Drug abuse, tolerance, and withdrawal continue to be a problem with benzodazepines. These phenomena also occur in the case of cocaine and morphine. The present work is designed to determine if the biological response mediated by the Bz1 or the Bz2 receptor subtype is responsible for abuse and for withdrawal in the Bz series. Bz1 receptors are proported to mediate the anxiolytic effects at BzR, while Bz2 receptors are reported to elicit the sedative-hypnotic effects. If one of these receptor subtypes is determined to be more important in abuse and/or withdrawal than the other, a better rational for drug design will be at hand. Recently, a series of rigid, planar dihydropyridodiindoles have been synthesized in our laboratory and shown to demonstrate potent affinity (5 nM) for benzodiazepine receptors (BzR) in vitro. It is felt these rigid analogs may conform to one receptor subsite, but will not be able to rotate, conformationally, to bind to a second subsite. Moreover, if either Bz1 or Bz2 selective ligands cue to cocaine or morphine in discriminative stimulus paradigms this would suggest that """"""""downstream"""""""" in the biological response there exists a common biological event for these drugs. The protocol here is to first characterize Bz receptors, and then to design ligands specific for either Bz1 or Bz2 sites. Information gained from the above studies will: 1) result in the preparation of selective benzodiazepine antagonists and nonbenzodiazepine agonists, 2) determine whether or not the pyridodiindoles 2 bind to the same inverse agonist receptor site(s) as beta-carbolines, 3) determine the effect of benzodiazepine receptors on anxiety, sleep, convulsions, and memory by providing a better understanding of the physiological processes influenced by the GABA/Bz/C1 complex. In addition, gram quantities of analogs related to 4, 7, 8, 9, and 10 will be prepared and screened in vivo to differentiate the intrinsic effects of beta-carbolines, and to design agents specific for interaction with one Bz receptor subtype in preference to another. These Bz subtype selective ligands can then be employed to determine whether the effects mediated by a Bz receptor subtype are the same effects that other drugs of abuse such as cocaine, alcohol and morphine cue to in discriminative stimulus paradigms.
| Hollinshead, S P; Trudell, M L; Skolnick, P et al. (1990) Structural requirements for agonist actions at the benzodiazepine receptor: studies with analogues of 6-(benzyloxy)-4-(methoxymethyl)-beta-carboline-3-carboxylic acid ethyl ester. J Med Chem 33:1062-9 |
