No abstract

The electrochemical reduction of 7-nitro-I ,4-benzodiazepin-2-ones and of their acid hydrolysis products, 2-amino-5-nitrobenzophenonesf was studied by polarography and cyclic voltammetry in a solventbuffer system containing pyridine, formic acid and tetramethylammonium chloride solution in order to elucidate the effect of the nature and position of the substituents on the reduction of the nitro group. It was found that these two types of compounds can be polarographically and voltammetrically distinguished and that their reduction mechanisms differ owing to a structural change in substituents located at a para-position relative to the nitro group. Based on polarographic and cyclic voltammetric data, reduction mechanisms for these two species are proposed in which the donoracceptor properties of the substituents and the importance of the chemical reactions associated with the electron-transfer steps are indicated. Keywords: 7-Nitro -I , 4-benzo diazep in -2-one; 2 -am in o-5-n itro benzop h e n o n e; p o la rog rap h y; cyclic vo ltam -Paper 91006086

Quantitative electronic structure-activity relations (QE-SAR) based on ab initio calculated atomic charge data have been investigated with respect to basis set influence on quality and predictability. A series of 11 nonpeptide dopioid receptor ligands has been utilized to study the basis set effect, and to determine the active center of these compounds. The geometries were fully optimized using the semiempirical method AM1. Net atomic charges obtained from ab initio MO calculations were used as electronic predictors. Multivariate adaptive regression splines were applied to the data matrix for the construction of QESAR models, whose predictability was rated by PRESS. The best model yielded a PRESS value of 0.08 and it was obtained using the atomic charges derived from the basis set 6-311G. This model contains the C(9), C(12), C(14), and O(19) atoms as predictors. The 3-21G basis set supplies an almost equivalent model and can be seen as an economic alternative, therefore, for large compounds.

A series of 21 d-opioid receptor ligands were studied to find a common active center related to the affinity towards the d-opioid receptor, based on AM1 molecular-orbital calculations. Multivariate adaptive regression splines (MARS) analysis was used to model the active center by atomic charges of selected sites as electronic descriptors. The results show that MARS is reliable in terms of PRESS. The resulting model is based on O(18), N(17), C(3), C(6), C(12), C(13), and C(16), indicating that the charges on these atoms have the strongest influence on the biological activity.Introduction. ± Multiple opioid receptors have been demonstrated through pharmacological and binding studies. Presently, the existence of at least three major types (m, k, d) of opioid receptors is generally acknowledged. Opioid receptors are involved in the modulation of a variety of physiological effects. Recent advances in the understanding of the biological functions of the d-opioid receptors have highlighted the important role of this receptor in the regulation of pain, and the search for d receptor ligands has been pursued in numerous laboratories [1 ± 3]. Because peptides are metabolically labile and have problems being orally absorbed, the design of nonpeptide ligands is desirable. The development of such ligands has improved our understanding of d-opoid receptors and facilitated the identification of new drugs. A d-selective agonist, BW373U86, a piperazine derivative, e.g., is reported to be a potent analgesic that does not produce physical dependence [4]. Another possible application of dopioid receptor agonists is a new therapeutic approach in Parkinson×s disease [5]. The chief criterion for the classification of an agonist effect as being opioid-receptormediated is the ability of naloxone or naltrexone to reversibly antagonize this effect in a competitive fashion. In addition to their use as pharmacological tools, selective nonpeptide opioid antagonists may have potential clinical applications in the treatment of a variety of disorders where endogenous opioids play a modulatory role. These include, e.g., disorders of food intake, shock, constipation, mental disorders, CNS injury, alcoholism, drug addiction, and immune function [6].Quantitative structure-activity relations (QSAR) have first been investigated systematically via the Hansch analysis [7], and they have increasingly proven their importance in chemistry and medicine [8]. Besides the more empirical descriptors commonly used in classical QSAR, quantum-chemically derived descriptors are an excellent alternative to the experiment-based ones [9], and their use in drug design is increasing. Atomic net charges obtained from semiempirical quantum methods have

No abstract