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 6,7. These agents are now felt to exert their physiological effects via the GABA/Bz/C1 complex 2,45. 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 17. The parent compound 2 (X=H) exhibited inverse agonist activity in vivo 17. Moreover, the 2-methoxy analog 4e was a potent proconvulsant, while the 2-chloro analog 4d demonstrated antagonist activity 17 similar to Ro 15-1788. It is felt these rigid analogs may conform to one receptor subsite, but will not be able to rotate, conformationally 21,61, to bind to a second subtype. In addition to enhanced Bz1 or Bz2 selectivity, these rigid planar, active ligands will be employed to model the pharmacophore for BzR. Based on these leads, different series of rigid 4, 7, 10, and semirigid 8, 9 analogs will be synthesized and tested in vitro (synaptosomal membranes) and in vivo (mice, rats, monkeys) to determine what structural requirements are necessary for potent selective (Bz1, or Bz2) inverse agonist, antagonist or agonist activity; the pyridodiinodoles 4 are important for they should possess long half-lives in vivo. Since the effects observed for beta-carbolines 12, 2 and 4e17 are different from those reported for Ro 15-1788 15, irreversible inhibitors based on these beta- carboline analogs will be prepared to label the """"""""proposed"""""""" 32,59,60 discrete inverse agonist/antagonist receptor site. Information gained from the above studies will: 1) result in preparation of selective benzodiazepine antagonists and nonbenzodiazepine agonists, 2) determine whether or not beta-carbolines bind to the same receptor sites(s) as do benzodiazepines, 3) determine the effect of benzodiazepine receptors on anxiety 4,9,22,23, sleep, 28 conclusions 27, and memory 29 by providing a better understanding of the physiological processes influenced by the GABA/Bz/C1 complex 2, 45. In addition, gram quantities of analogs related to 4, 7, 8, 9, and 10 will be prepared and screened in vivo to separate out the intrinsic effects of beta-carbolines, and to design agents specific for interaction with one Bz receptor subtype in preference to another.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH036644-05
Application #
3375897
Study Section
Neurosciences Research Review Committee (BPN)
Project Start
1988-09-30
Project End
1993-08-31
Budget Start
1989-09-01
Budget End
1990-08-31
Support Year
5
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Wisconsin Milwaukee
Department
Type
Schools of Arts and Sciences
DUNS #
City
Milwaukee
State
WI
Country
United States
Zip Code
53201
Martin, M J; Trudell, M L; Diaz Arauzo, H et al. (1992) Molecular yardsticks. Rigid probes to define the spatial dimensions of the benzodiazepine receptor binding site. J Med Chem 35:4105-17
Allen, M S; Skolnick, P; Cook, J M (1992) Synthesis of novel 2-phenyl-2H-pyrazolo[4,3-c]isoquinolin-3-ols: topological comparisons with analogues of 2-phenyl-2,5-dihydropyrazolo[4,3-c]quinolin-3(3H)-ones at benzodiazepine receptors. J Med Chem 35:368-74
Allen, M S; Tan, Y C; Trudell, M L et al. (1990) Synthetic and computer-assisted analyses of the pharmacophore for the benzodiazepine receptor inverse agonist site. J Med Chem 33:2343-57
Trudell, M L; Lifer, S L; Tan, Y C et al. (1990) Synthesis of substituted 7,12-dihydropyrido[3,2-b:5,4-b']diindoles: rigid planar benzodiazepine receptor ligands with inverse agonist/antagonist properties. J Med Chem 33:2412-20
Diaz-Arauzo, H; Cook, J M; Christie, D J (1990) Synthesis of 10,11-dihydroxydihydroquinidine N-oxide, a new metabolite of quinidine. Preparation and 1H-nmr spectroscopy of the metabolites of quinine and quinidine and conformational analysis via 2D COSY nmr spectroscopy. J Nat Prod 53:112-24
Allen, M S; Hagen, T J; Trudell, M L et al. (1988) Synthesis of novel 3-substituted beta-carbolines as benzodiazepine receptor ligands: probing the benzodiazepine receptor pharmacophore. J Med Chem 31:1854-61
Hagen, T J; Skolnick, P; Cook, J M (1987) Synthesis of 6-substituted beta-carbolines that behave as benzodiazepine receptor antagonists or inverse agonists. J Med Chem 30:750-3
Trudell, M L; Basile, A S; Shannon, H E et al. (1987) Synthesis of 7,12-dihydropyrido[3,4-b:5,4-b']diindoles. A novel class of rigid, planar benzodiazepine receptor ligands. J Med Chem 30:456-8
Takada, K; Winger, G; Cook, J et al. (1986) Discriminative and aversive properties of beta-carboline-3-carboxylic acid ethyl ester, a benzodiazepine receptor inverse agonist, in rhesus monkeys. Life Sci 38:1049-56
Takada, K; Winger, G D; Cook, J et al. (1986) Discriminative and aversive stimulus effects of beta-carboline ethyl ester in rhesus monkeys. NIDA Res Monogr 67:119-24

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