Terms Of Structure-activity Relationships Research Articles

Structure-activity relationships of phenytoin-like anticonvulsant drugs.

A limited series of compounds structurally related to phenytoin has been tested in the maximal electroshock seizure (MES) test in order to define the impact on their antiepileptic activity of reducing the ability to form a hydrogen bond. A net stepwise decrease of the anticonvulsant activity was observed when the hydantoin ring structure was altered into succinimide and pyrrolidinone and when these rings were N-methylated. The pharmacological data analyzed in terms of structure-activity relationships (SAR) indicate the importance of the capability of forming hydrogen bonds. Further insight into the molecular mode of action of phenytoin was gained by a 13C NMR study of three phenytoin analogues deuterated in one of the phenyl groups, i.e., o-, m-, p-deuteriophenytoin. This approach allowed the unambiguous assignment of the chemical shifts of the ortho, meta, para, and ipso carbons. Measurement of the T1 relaxation times provided a value of 0.2 s for the para carbon and 0.8 s for the meta and ortho carbons of the phenytoin phenyl rings. These data are consistent with the view that the two phenyl groups possess a certain degree of rotational freedom along the para-ipso axis. More generally, the present results, as well as some literature data, support the concept that the ability to form hydrogen bonds as well as a certain degree of motional freedom of the phenyl groups are important SAR features in antiepileptic phenytoin-like drugs.

Regulation of cytochrome P-450. Immunochemical quantitation of eight isozymes in liver microsomes of rats treated with polybrominated biphenyl congeners.

Specific immunochemical techniques were used to quantitate the levels of eight isozymes of cytochrome P-450 (P-450) and epoxide hydrolase in liver microsomes of untreated rats and rats treated with phenobarbital, 3-methylcholanthrene, a mixture of these two compounds, nine individual polybrominated biphenyl (PBB) congeners, and a commercial mixture of PBBs. Levels of two 3-methylcholanthrene-inducible P-450s (designated P-450 beta NF-B and P-450 beta NF/ISF-G) varied over two orders of magnitude and were highly correlated. The levels of four phenobarbital-inducible P-450s (designated P-450PB-B, P-450PB-C, P-450PB-D, and P-450PB/PCN-E) were all correlated to each other. The level of one form, P-450UT-A, which was present at substantial levels in untreated rats, was inversely correlated to the levels of P-450 beta NF-B and P-450 beta NF/ISF-G. Among the PBB congeners which were examined, the presence of bromine at carbons o to the biphenyl bridge favored the induction of P-450PB-B, P-450PB-C, P-450PG-D, and P-450PB/PCN-E but did not necessarily eliminate the ability to induce P-450 beta NF-B and P-450 beta NF-ISF-G. PBB congeners with 2,2'-dibromo substitution induced P-450 beta NF-B and P-450 beta NF/ISF-G if one of the biphenyl rings contained bromines at positions 2,3, and 4. The induction of P-450UT-F was found to occur to a small extent with three of the compounds and is not readily explained in terms of structure-activity relationships. Although correlations were found among levels of some of the forms of P-450, several important exceptions were noted in relative levels of the individual enzymes. While the correlative data are useful in predicting induction patterns, all eight forms of P-450 appear to be independently regulated to some extent.

Synthesis of peptides by the solid-phase method. IV. Des-Arg(9)-bradykinin and analogs.

We have synthesized a series of 19 analogs of the octapeptide fragment of bradykinin (BK), des-Arg 9-bradykinin, in order to perform a structure-activity study of this peptide on the newly discovered B1 receptor of bradykinin. The first time, each residue of the octapeptide was replaced by L-alanine to pinpoint biologically important residues. Thereafter, both phenylalanine residues in positions 5 and 8 were substituted by L-tyrosine methyl ether, L-cyclohexylalanine, D-phenylalanine, and L-leucine. This paper describes the synthesis of the analogs by the solid phase method. A Beckman peptide synthesizer was used to assemble the peptides on the resin support. Couplings were performed by the symmetrical anhydribe procedure. After cleavage with liquid HF, the peptides were purified by ion-exchange chromatography on carboxymethyl-cellulose and by gel filtration on Bio-Gel P2 resin. The purity of the octapeptides was then checked by tic, paper electrophoresis, amino acid analysis, and elemental analysis. The new peptides were tested on the rabbit aorta in order to evaluate their kinin-like activities and to see if they act as antagonist. The results of the biological assays are discussed in terms of structure-activity relationships.

Leaving group effects i butyrylcholinesterase reaction with organophosphorus inhibitors

The kinetic constants k 2 , K Q and the second-order rate constant k 1 of butyrylcholinesterase (acylcholine acylhydrolae, EC 3.1.1.8) inhibition by organophosphorus compounds (C 2H 5O) 2P(O)SX, with both ionic and non-ionic substituents X, were determined at 25°C and pH 7.5 in 0.15 M KCl. The data were analysed in terms of structure-activity relationships and the roles of the leaving group inductive effect and hydrophobicity in the enzyme specificity were established. This made possible calculations of the actual contribution of the substituent onic charge in the effectiveness of butyrylcholinesterase action. On the basis of the structure-activity relationships for butyrylcholinesterase and acetylcholinesterase the specificities of the enzymes are compared and some common features are discussed.