Pharmaceutica acta Helvetiae最新文献

Azodyes, derivatives of 1,2,4-triazole and pyrocatechine: 3-(3′,4′-dihydroxyphenylazo-1′)-1,2,4-triazole (TRIAP) and 3-(3′,4′-dihydroxyphenylazo-1′)-5-mercapto-1,2,4-triazole (METRIAP), were used for spectrophotometric determination of Al. in composite pharmaceutical preparations. In aqueous-methanolic solution at pH 6.20–6.50 Al ions form stabile, orange chelates. Molar ratio L:Al. is 2:1 (TRIAP) or 3:1 (METRIAP) and stability constants, expressed by log K, are 12,604 (METRIAP) and 8,440 (TRIAP). Other components of these preparations, particularly Mg, do not disturb Al determination. The determination results were statistically calculated and compared with those obtained by the method of atomic absorption spectrophotometry (AAS). The advantage of the developed method is easy synthesis of reagents, simple analytical procedure, stability of formed complexes, good reproducibility and accuracy of results. Using TRIAP or METRIAP the elaborated spectrophotometric method is more accurate than AAS method, for defined purpose.

The NMDA receptor is an ionotropic receptor complex widely distributed in the central nervous system and its activation, particularly in hypoxic conditions such as stroke, traumatic head injury and hypoglycemia, results in a massive influx of calcium ions into the post-synaptic neurones, leading to cell death through the activation of several neurotoxic cascades. The NMDA receptor is a unique ionotropic receptor complex because its activation requires the simultaneous binding of glutamate and glycine and selective antagonists at the glycine binding site are endowed with a better side-effect profile than competitive NMDA antagonists. Then, considerable efforts have been devoted to find potent and selective ligands, resulting in the identification of several classes of glycine antagonists. The research at Glaxo Wellcome has been aimed at the identification of novel in vivo active glycine antagonists, and led to the synthesis and pharmacological characterization of a number of novel, potent and systemically active compounds belonging to different chemical classes.

Chemokines are a superfamily of proteins that play a central role in immune and inflammatory reactions and in viral infections. About 50 different chemokines divided in four subfamilies are known, CXC, CC, C, and CX3C. Chemokine receptors can function as entry/fusion co-receptors for human immunodeficiency virus (HIV)-1 infection, and regulation of receptor expression by cytokines may be relevant for viral infection. Posttranslational processing of chemokines can profoundly affect their interaction with receptors. The serine protease CD26/dipeptidyl-peptidase IV (CD26/DPP IV) removes NH₂-terminal dipeptides from several chemokines and profoundly affect their biological activity. Kaposi's sarcoma (KS)-associated herpes virus 8 encodes for three chemokine-like proteins that show homology with MIP cluster of CC chemokines. These viral chemokines possess a partial agonist activity for certain chemokine receptors and may function as receptor antagonists. This biological activity could represent a strategy developed by the virus to subvert immunity impairing the generation of an effective anti-viral immune response.

Neuronal nicotinic acetylcholine receptors (nAChRs) are a class of ion channels with significant potential as molecular targets for the design of drugs to treat a variety of CNS disorders. The discovery that neuronal nAChRs are further subdivided into multiple subtypes suggests that drugs which act selectively at specific nAChR subtypes might effectively treat Parkinson's disease (PD), Alzheimer's disease (AD), schizophrenia, ADHD, depression, anxiety or pain without the accompanying adverse side effects associated with non-selective agents such as nicotine (1) and epibatidine. Altinicline (SIB-1508Y) is a novel, small molecule designed to selectively activate neuronal nAChRs and is undergoing clinical evaluation for the treatment of PD. It was selected from a series of compounds primarily on the basis of results from functional assays, including (a) measurement of Ca²⁺ flux in stable cell lines expressing specific recombinant human neuronal nAChR subtypes; (b) determination of in vitro and in vivo neurotransmitter release; (c) in vivo models of PD. Biological data on both altinicline and the series of compounds from which it was selected are reported.

The ability of trophic factors to regulate developmental neuronal survival and adult nervous system plasticity suggests the use of these molecules to treat neurodegeneration associated with human diseases, such as Alzheimer's, Huntington's and Parkinson's disease, of amyotrophic lateral sclerosis and peripheral sensory neuropathies. Recent biological data on the neutrotrophins NGF and BDNF, on GDNF, CNTF and IGF-I are discussed together with first results from clinical trials. Literature is presented on the three-dimensional structures of these trophic factors and on models proposed for ligand–receptor interactions. Substantial progress has been made in the understanding of the mechanisms of apoptosis. The cascade consisting of interaction of apoptosis-inducing ligands with death receptors, the coupling of this complex to adaptor proteins via death domains, the further recruitment of procaspases via death effector or caspase recruitment domains and the execution of cell death via the effector caspases is briefly outlined.

The subdivision of α adrenoceptors into the α₁ and α₂ classes was the impetus for the design of the selective α₁-adrenoceptor antagonists, which remain useful antihypertensives. α₂-Adrenoceptor agonists also have application as antihypertensive drugs, based on their ability to reduce sympathetic outflow. Likewise, subdivision of the β adrenoceptors has lead to the development of selective β₁-adrenoceptor antagonists as antihypertensives and selective β₂ agonists as bronchodilators. In the past decade, both the α₁ and α₂ adrenoceptors have been further subdivided, each into three subclasses. In addition, there is strong functional evidence to suggest the presence of additional adrenoceptor subtypes, such as the “α_1L” adrenoceptor and “β₄” adrenoceptor. α_1A (or α_1L)-Adrenoceptor antagonists have been evaluated for benign prostatic hyperplasia (BPH), and selective α_1A agonists for stress incontinence. Gene knockout experiments in mice suggest an important role for the α_1B adrenoceptor in the control of vascular tone. Hence, selective α_1B antagonists may offer a new approach toward hypertension. Although targeting of specific adrenoceptors can be used to optimize the therapeutic profile of a drug, there are also cases where blockade of multiple adrenoceptors is desirable, as with the α/β-adrenoceptor antagonist carvedilol in congestive heart failure. It is possible that combination of affinities for selected adrenoceptor subtypes within a single molecule may be desirable for certain applications.

Ligands for the allosteric site of acetylcholine M₂ receptors are able to retard the dissociation of simultaneously bound ligands for the orthosteric site. This effect promotes receptor occupation by the orthosteric ligand. The allosteric effect opens various therapeutic perspectives, e.g., in organophosphorus poisoning. The aim of our studies was to optimize the affinity of the modulators for the common allosteric binding site of muscarinic M₂ receptors, the orthosteric site of which was liganded with the N-methylscolopamine. The phthalimido substituted hexane-bisammonium compound W84 served as a starting point. Previous molecular modelling studies revealed two positive charges and two aromatic imides in a sandwich-like arrangement to be essential for a high allosteric potency. A three-dimensional quantitative structure activity relationship (3D QSAR) analysis predicted compounds with substituents of increasing size on the lateral imide moieties to enhance the affinity for the allosteric binding site. Thus, we synthesized and pharmacologically evaluated compounds bearing “saturated” phthalimide moieties as well as phthalimidines with substituents of systematically increasing size in position 3 or on the aromatic ring at one or both ends of the molecule. Within each series, QSAR could be derived: 1. “Saturation” of the aromatic ring of the phthalimide moiety results in less potent compounds. 2. Increasing the size of the substituents in position 3 of the phthalimide enhances the potency. 3. Putting substituents on the aromatic part of the phthalimide increases the potency more effectively: the introduction of a methyl group in position 5 gave a compound with a potency in the nanomolar concentration range which was subsequently developed as the first radioligand for the allosteric binding site.

Death receptors belong to the TNF receptor family and are characterised by an intracellular death domain that serves to recruit adapter proteins such as TRADD and FADD and cysteine proteases such as Caspase-8. Activation of Caspase-8 on the aggregated receptor leads to apoptosis. Triggering of death receptors is mediated through the binding of specific ligands of the TNF family, which are homotrimeric type-2 membrane proteins displaying three receptor binding sites. There are various means of modulating the activation of death receptors. The status of the ligand (membrane-bound vs. soluble) is critical in the activation of Fas and of TRAIL receptors. Cleavage of membrane-bound FasL to a soluble form (sFasL) does not affect its ability to bind to Fas but drastically decreases its cytotoxic activity. Conversely, cross-linking epitope-tagged sFasL with anti-tag antibodies to mimic membrane-bound ligand results in a 1000-fold increase in cytotoxicity. This suggests that more than three Fas molecules need to be aggregated to efficiently signal apoptosis. Death receptors can also be regulated by decoy receptors. The cytotoxic ligand TRAIL interacts with five receptors, only two of which (TRAIL-R1 and -R2) have a death domain. TRAIL-R3 is anchored to the membrane by a glycolipid and acts as a dominant negative inhibitor of TRAIL-mediated apoptosis when overexpressed on TRAIL-sensitive cells. Intracellular proteins interacting with the apoptotic pathway are potential modulators of death receptors. FLIP resembles Caspase-8 in structure but lacks protease activity. It interacts with both FADD and Caspase-8 to inhibits the apoptotic signal of death receptors and, at the same time, can activate other signalling pathways such as that leading to NF-κB activation.