Anticholinesterase activity and structure activity relationships of a new series of hemicholinium-3 analogs

Piperidine derivatives of hemicholinium-3 were synthesized and included the following spacing groups between the bis-cationic heads: trans,trans-bicyclohexyl, phenanthrene, naphthalene and biphenyl. Anticholinesterase activity was determined using rat striatal synaptosomal cholinesterase, bovine erythrocyte acetylcholinesterase and horse serum butyrylcholinesterase. Hemicholinium-3 has little anticholinesterase activity but when the choline moiety of hemicholinium-3 is replaced with selected heterocyclic amine ring systems active inhibitors can be obtained. Results in this communication identify several quaternary amines which are equipotent with physostigmine for inhibition of cholinesterase. Several tertiary amines were also found to be active. Optimal anticholinesterase activity of these piperidine derivatives appear to be related to the necessity of 14 A interatomic distance between the cationic heads as well as C = O substitution in the phenylethyl spacing moiety. Reduction of C = O to secondary alcohol or CH2 results in decreased activity. The anticholinesterase activity is not only related to internitrogen distance and C = O substitution but also structural planarity and positional isomerism of the quaternary cationic head.     

MAOI activity of some novel series of substituted thiazol-2-yl-hydrazines.

Three series of 2-thiazolylhydrazines were synthetized and evaluated for their MAO inhibitory (MAOI) activity, both by in vivo tests, to assay their influence on several MAOI activity-related parameters (the variation on blood pressure induced by tyramine and clonidine and L-amfetamine-induced hypermotility) and in vitro tests, to assay their effect on rat brain mitochondria by a kinuramine fluorimetric assay. In vivo, all the tested compounds significatively influenced the evaluative parameters used. As regards in vitro test, all compounds displayed MAOI activity at a concentration of 1.10(-4) mol.l-1, which was significant in several cases. In the discussion of the results, the influence of the structure on the biological activity of the prepared compounds was delineated.     

Structure-carcinogenic activity relationships in the Benz [a] anthracene series.

The syntheses of 1,7,12-trimethyl- and 2,7,12-trimethylbenz[a]anthracenes are described. The lack of carcinogenic activity of these compounds is discussed in relationship to the carcinogenic activity of other substituted benz[a]anthracenes.     

Studies on the duration of local anaesthesia: structure/activity relationships in a series of homologous local anaesthetics

When the number of carbon atoms on the piperidine-nitrogen of the mepivacaine molecule was increased up to four or five carbons, the toxicity of the compounds and the duration of their local anaesthetic effects were increased. With longer N-alkyl-chains, the general toxicity and the local anaesthetic potency - but not the tissue toxicity - were reduced. In dental infiltration anaesthesia only the short-chain compounds offered an acceptable local anaesthesia. In these tests, the medium-chain compounds had a very unfavourable quotient between dental anaesthesia and soft tissue anaesthesia, while the long-chain compounds could not be tested at all in man because of their tissue irritating properties.     

Evolution of a series of peptidoleukotriene antagonists: synthesis and structure/activity relationships of 1,3,5-substituted indoles and indazoles

1,3,5-Substituted indoles and indazoles have been studied as receptor antagonists of the peptidoleukotrienes. The best of these compounds generally had a methyl group at the N1 position, a [(cyclopentyloxy)carbonyl]amino or 2-cyclopentylacetamido or N'-cyclopentylureido group at the C-5 position, and an arylsulfonyl amide group as part of the acidic chain at the C-3 position of the ring. Such compounds had in vitro dissociation constants (KB) in the range 10(-9) - 10(-11) M on guinea pig trachea against LTE4 as agonist and inhibition constants (Ki) less than or equal to 10(-9) M on guinea pig parenchymal membranes against [3H]LTD4. A number of compounds were orally effective at doses less than or equal to 1 mg/kg in blocking LTD4-induced "dyspnea" in guinea pigs. Compound 45 [N-[4-[[5-[[(cyclopentyloxy)carbonyl]-amino]-1-methylindol-3- yl]methyl]-3-methoxybenzoyl]-2-methylbenzenesulfonamide, ICI 204,219; pKB = 9.67 +/- 0.13, Ki = 0.3 +/- 0.03 nM, po ED50 = 0.3 mg/kg] is currently under clinical investigation for asthma. In the indole series, certain alkylsulfonyl amides possessing a 3-cyanobenzyl substituent at the N-1 position (60, 61) were produced that had KB less than or equal to 10(-9) M on guinea pig trachea.     

Electronic-topological study of the structure-activity relationships in a series of steroids with mineralocorticoid binding affinity

Conformational analysis and quantum chemical calculations were carried out using molecular mechanics (MMP2) and semi-empirical quantum chemistry (CNDO/2) methods for 51 steroid homologues belonging to a series of 17-spirolactones. Matrices called Electronic-Topological Matrices of Conjunction (ETMCs) were formed using data obtained from quantum chemical calculations. A structural fragment of activity was identified in the series of steroids. As seen from the fragment's properties, active compounds are characterized by the presence of two atoms of oxygen, O1 and O3, which are situated at a distance of 13.5 A and possess high negative charges (-0.29 to -0.31 e).     

Synthesis and structure-activity relationships of a series of novel benzopyran-containing platelet activating factor antagonists.

A class of N-substituted tetrahydrobenzopyrano[3,4-c]pyridines, I, have been identified as antagonists of platelet activating factor (PAF). The structural features essential for PAF binding were determined by systematic modification of three sites in the molecule. While O-alkyl analogues had little effect on binding potency, N-alkyl analogues exhibited a wide range of activity. Structural changes in the core ring system generally resulted in a loss of binding activity. Optimization of the N- and O-substituents resulted in the analogues 25-27 which exhibited Ki values ranging between 131 and 167 nM in a [3H]PAF binding assay. Compound 23 was also active in a model of PAF-induced shock in the mouse following intravenous administration.     

P45017α抑制剂──17位取代甾体化合物的三维定量构效关系

目的　建立P450_17α的17位取代甾体抑制剂的三维定量构效关系,为设计新的、更有效的抑制剂提供理论依据。方法和结果　利用比较分子力场方法,建立了P450_17α抑制剂的三维定量构效关系模型。交叉验证回归系数R2CV、非交叉验证回归系数R2 和标准偏差SEE分别为0.538,0.799和0.257。说明该系列化合物分子周围立体场和静电场的分布与生物活性间有良好的相关性。用该模型对本室合成的3个化合物进行活性预测,结果与实测值相符。结论　所得模型支持了假设的抑制剂作用机理和作用模型。所得CoMFA模型有一定的预测能力,可用来指导设计新的P450_17α抑制剂     

Synthesis and anti-cancer activity of some novel C-17 analogs of ursolic and oleanolic acids

A series of seventeen novel analogs of ursolic and oleanolic acid were synthesized (60–98 %), and evaluated for their anti-cancer potential against a panel of eight human cancer cell lines. Compounds (3–10) showed comparable or better activities than their respective parent compounds against SiHa and HeLa (Cervix), A-549 (Lung), and IMR-32 (Neuroblastoma) cancer cell lines. Significantly, among the bromoalkyl esters (11–19), compound 13 showed promising anti-cancer activity against Leukemia THP-1 cell line at 10 μM concentration. In this series, it is interesting to note that the increase in chain length has an adverse effect on the activity.     

Structure activity relationships in a series of anti-neoplastic dinitrophenyl aziridines--protein binding studies

The reversible binding of a series of antineoplastic 2,4-dinitrophenylaziridines to bovine serum albumin has been studied. The methods of gel filtration and continuous diafiltration were used to estimate the amount bound and the reversibility of binding. The compounds were shown to be weakly but reversibly bound and the extent of binding correlated well with biological activity and molecular structure.     

Tachykinins and tachykinin receptors: structure and activity relationships

In addition to the classical neurotransmitters, acetylcholine and noradrenaline, a wide number of peptides with neurotransmitter activity have been identified in the past few years. Among them, the tachykinins substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) appear to act as mediators of nonadrenergic, noncholinergic (NANC) excitatory neurotransmission. Tachykinins interact with specific membrane proteins, belonging to the family of G protein-coupling cell membrane receptors. Until now, three tachykinin receptors termed NK1 (NK1R), NK2 (NK2R) and NK3 (NK3R) have been cloned in different species. A large amount of reports suggests that these peptides are involved in nociception and neuroimmunomodulation, and in the development of different diseases such as bronchial asthma, inflammatory bowel syndrome and psychiatric disorders. Tachykinin receptor antagonists are therefore promising, therapeutically relevant agents. However, and in spite of extensive research, the obtention of selective antagonists of tachykinin receptors have revealed very difficult. An understanding of how ligands interact with their receptors is essential to permit a rational design of compounds acting selectively at the tachykinin receptor level. The major aim of the present article is to review the structure-activity data that exist for tachykinins and their receptors, with the purpose of getting insight into basic structural requirements that determine ligand/receptor interaction.     

Relationships between structure and vascular activity in a series of benzylisoquinolines

1. In the present work, the properties of 3-methyl isoquinoline, 3,4-dihydropapaverine, tetrahydropapaverine and tetrahydropapaveroline were compared with those of papaverine and laudanosine. The work includes functional studies on rat isolated aorta contracted with noradrenaline, caffeine or KC1, and a determination of the affinity of the compounds for α₁-adrenoceptors and calcium channel binding sites, with [^#H]-prazosin, [^#H]-nitrendipine and [^#H]-(+)-cis-diltiazem binding to rat cerebral cortical membranes. The effects of papaverine derivatives on the different molecular forms of cyclic nucleotide phosphodiesterases (PDE) isolated from bovine aorta were also determined.
2. The three papaverine derivatives show greater affinity than papaverine for the [^#H]-prazosin binding site. They are therefore more selective as inhibitors of [^#H]-prazosin binding as opposed to [^#H]-(+)-cis-diltiazem, while papaverine appears to have approximately equal affinity for both. [^#H]-nitrendipine binding was not affected by either papaverine or papaverine derivatives in concentrations up to 100 μM. 3-Methylisoquinoline had no effect on any of the binding sites assayed.
3. Contractions evoked by noradrenaline (1 μM) in rat aorta were inhibited in a concentration-dependent manner by 3,4-dihydropapaverine, tetrahydropapaverine and with a lower potency, by tetrahydropapaveroline. In Ca²⁺-free solution, tetrahydropapaverine and to a lesser extent, tetrahydropapaveroline, inhibited the noradrenaline (1 μM) evoked contraction in a concentration-dependent manner and did not modify the phasic contractile response evoked by caffeine (10 mM). This suggests that these alkaloids do not act at the intracellular level, unlike papaverine which inhibits the contractile response to caffeine and noradrenaline.
4. Inositol phosphates formation induced by noradrenaline (1 μM) in rat aorta was inhibited by tetrahydropapaverine (100 μM) and tetrahydropapaveroline (300 μM), thus suggesting that α_1D-adrenoceptors are coupled to phosphoinositide metabolism in rat aorta.
5. Unlike papaverine, which has a significant effect on all the PDE isoforms, the three alkaloids assayed did not have an inhibitory effect on the different forms of PDE isolated from bovine aorta.
6. These results provide evidence that papaverine derivatives with a partially or totally reduced isoquinoline ring have a greater affinity for α₁-adrenoceptors and a lower affinity for benzothiazepine sites in the Ca²⁺-channel than papaverine. This structural feature also implies a loss of the inhibitory activity on PDE isoforms. The planarity of the isoquinoline ring (papaverine) impairs the interaction with the α₁-adrenoceptor site and facilitates it with the Ca²⁺-channels and PDEs, whereas the more flexible tetrahydroisoquinoline ring increases the binding to α₁-adrenoceptors.