The 3-substituted beta-carbolines 2-4 and 5-7 were prepared from 3-amino-beta-carboline (8) in one step via diazotization, followed by reaction with the appropriate nucleophile in order to determine their binding affinity for benzodiazepine receptors (BzR). All three of the 3-alkoxy-beta-carbolines 2 (IC50 = 124 nM), 3 (IC50 = 24 nM), and 4 (IC50 = 11 nM) have high affinities for BzR. The beta-carbolines substituted with electron-withdrawing groups including 5 (Cl; IC50 = 45 nM), 6 (NO2; IC50 = 125 nM), and 7 (N = C = S; IC50 = 8 nM) also had high affinities for BzR. The affinities of 5-8 clearly indicate that a carbonyl moiety at position 3 of a beta-carboline is not required for high-affinity binding to BzR. These findings have led to the development of a model for the binding of ligands to an inverse agonist domain at BzR. This model is supported by the recent synthesis of 3-ethoxy-beta-carboline (3), a potent, long-lived partial inverse agonist, and 7, an irreversible BzR ligand.
, 2749 (1983). Bis(di-tert-butylmethyl) diselenide (4) is the first example of a diselenide with an abnormal obtuse dihedral angle resulting from steric crowding. Its value was determined to be 112.1(3)" by X-ray crystallography, as compared with typical dihedral angles of 74-87" for other diselenides. The uv spectrum of 4 supports a similar conformation in solution. ence for conformations where the dihedral angle (C-Se-Se/ Se-Se-C) ( Fig. 1) is acute and lies within the range of 74"-87", except when constrained by the imposition of a cyclic structure. Thus, the cyclic diselenide 2 displays a dihedral angle of only 56" (7).The effects of very bulky substituents on the conformations of diselenides have not been investigated by crystallographic methods. To our knowledge, even the most hindered diselenide with a known crystal structure, bis(diphenylmethy1) diselenide (3), exhibits a normal, acute dihedral angle of 82" (2). More recently, Barton and co-workers (8) reported the preparation of bis(di-tert-butylmethyl) diselenide (4), a stable, crystalline substance. An examination of a model of this compound indicated that steric interactions might be severe enough to result in significant departure from the usual preferred diselenide geometry. Steric congestion could be relieved either through an increase in the dihedral angle or by lengthening of the bonds in the C-Se-Se-C moiety. It is also interesting to note that the analogous triselenide 5, whose crystal structure has been reported (9), displays normal C-Se and Se-Se bond lengths and moderate extension of the two C-Se-Se/Se-Se-Se dihedral angles to 100.6" and 86.9". It is evident, however, that
FIG. I . Conformation of a typicaI diselenide.the interposition of the third contiguous selenium atom. To ascertain the extent of such effects in diselenide 4, we undertook its X-ray crystallographic structure determination. We now report the first example of a diselenide with an obtuse dihedral angle. Since molecular conformations may differ in the solid state and in solution, we also endeavoured to confirm that diselenide 4 has an abnormal dihedral angle in solution. Compression of the dihedral angle from the preferred value of 74-87" raises the energy of the ground state of a diselenide but has little effect on the excited state (10). Thus, cyclic diselenides such as 2 exhibit strong bathochromic shifts as a result of the lowered excitation energy (1 1). A similar phenomenon might be expected in the case of a diselenide in which destabilization of the ground state results from the enlargement rather than the compression of the dihedral angle, although such an effect has not yet been documented. We believe that diselenide 4 constitutes the first such example, as it displays a marked bathochromic shift compared to other, less crowded acyclic diselenides.any steric effects resulting from the interaction of the bulky Experimental substituents are greatly reduced in the triselenide Bis(di-tert-butylmethyl) diselenide (4) was by the method of Barton and co-workers (8) int...
The molecular structures of cyheptamide and 3-hydroxy-3- phenacyloxindole were determined by X-ray diffraction methods. The amide group in both compounds exhibits delocalization of the pi-electrons over the three atoms (N, C, and O), while the bond linking the amide to the tetrahedral carbon atom is a single bond. These structural features are also present in two drugs used for the treatment of generalized tonic-clonic ( GTC ) seizures, namely, carbamazepine and diphenylhydantoin. The shapes of cyheptamide , 3-hydroxy-3- phenacyloxindole , and carbamazepine have three features that are the same and can be simultaneously overlapped, the amide and two hydrophobic regions, whereas diphenylhydantoin fits two of the three regions at one time. These structural and electronic features are analyzed in light of current models for anticonvulsant activity.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.