1,721,055 research outputs found
The Camerino symposium series (1978-2013): a privileged observatory of receptorology development
No full textThe organizers of the Camerino Receptor Symposia survey the development of receptorology. They trace the
course from the first Symposium in 1978, which laid the foundation for Pirenzepine, the first selective muscarinic
antagonist, to the 2010 Symposium, which highlighted the utility of functional simple domain antibodies
(nanobodies) as novel G Protein-Coupled Receptor (GPCR) modulators. This 30-year period sees the acceptance of
terms such as G-protein, auto- and heteroreceptors, site-directed mutagenesis, chimeric receptors, constitutive
activity, inverse agonism, and orphan receptors. GPCRs are finally a reality and Langley and Ehrlich, if they returned
to their laboratories, would be proud of how their intuitions have been realized
Agonists and antagonists targeting the different alpha(2)-adrenoceptor subtypes
No full textChemical and biological strategies have provided evidence for α2-receptor heterogeneity, to date classified in three different subtypes, α2A, α2B, and α2C. These are widely distributed throughout the body and mediate numerous effects; therefore, the potential therapeutic indications of agonists and antagonists are numerous. Nevertheless, the lack of subtype-selectivity of the well-known compounds represents a major limit for their use. SAR studies may help to design new and more selective drug
3-Phenyl analogues of 2-[[[2-(2,6-Dimethoxyphenoxyethyllamino]methyl]-1,4-benzodioxan (WB 4101) as highly selective alpha1-adrenoreceptor antagonists1
No full textPhendioxan represents, until now, the most selective alpha1-adrenoreceptor antagonist in in vitro experiments and it might be not only a useful tool in the characterization of alpha-adrenoreceptor subtypes but also a lead compound for the design of more selective and more potent antagonist
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Enantiomers of 6,6-diphenyl-1,4-dioxane derivatives to highlight stereochemical requirements for selective alpha1D-AR and 5- HT1A receptor recognition
No full textSeveral examples support the concept that modest chemical modifications can drastically alter the biological profile of the compounds both regard to different receptor systems and inside the same system, leading to unexpected and interesting results. This consideration has prompted Boström et al. to question whether structurally similar ligands bind in a similar fashion.1
In a recent study about new 6,6-diphenyl-1,4-dioxane derivatives, we demonstrated that small modifications on the 2-phenoxyethyl moiety induced significant biological changes. In fact, the unsubstituted 1, the 2-methoxy 2, and the 2,6-dimethoxy 3 analogues proved to be endowed with high cytotossic effect, α1D-adrenergic receptor (α1D-AR) antagonist and 5-HT1A receptor full agonist activity, respectively.2
It is well known that stereochemistry can quantitatively and qualitatively influence ligand biological profile3 and that α1D- and 5-HT1A receptor interactions result highly stereospecific. Therefore, to obtain indications for identifying further structural and stereochemical requirements for selective α1D and 5-HT1A receptor recognition, we thought it of interest to prepare and test the enantiomers of 2 and 3. The enantiomers of 1 have been prepared to verify whether there is a relationship between stereochemistry and anticancer activity.
1. Boström, J.; Hogner, A.; Schmitt, S. Do structurally similar ligands bind in a similar fashion? J. Med. Chem. 2006, 49, 6716-6725.
2. Quaglia, W.; Piergentili, A.; Del Bello, F.; Farande, Y.; Giannella, M.; Pigini, M.; Rafaiani, G.; Carrieri, A.; Amantini, C.; Lucciarini, R.; Santoni, G.; Poggesi, E.; Leonardi, A. Structure-activity relationships in 1,4-benzodioxan-related compounds. 9. From 1,4-benzodioxan to 1,4-dioxane
ring as a promising template of novel α1D-adrenoreceptor antagonists, 5-HT1A full agonists, and
cytotoxic agents. J. Med. Chem. 2008, 51, 6359-6370.
3. Caner, H.; Groner, E.; Levy, L. Trends in the development of chiral drugs. Drug Disc. Today 2004, 9, 105-110
Rapid novel divergent synthesis and muscarinic agonist profile of all four optical isomers of N,N,N-trimethyl(6-methyl-1,4-dioxan-2-yl)methanaminium iodide.
No full textTwo stereoselective parallel divergent four-step procedures to obtain all four enantiomeric forms of N,N,N-trimethyl(6-methyl-1,4-dioxan-2-yl)methanaminium iodide were developed. Enantiomeric purity was determined by quantitative 1H NMR spectroscopy in the presence of the chiral shift reagent (+)-MTPA. The biological profile of the obtained compounds was evaluated at all muscarinic receptor subtypes by binding and functional assays
Age-related Changes in the Density of Muscarinic Cholinergic M1 and M2 Receptor Subtypes in Pyramidal Neurons or the rat Hippocampus
No full textAge-dependent changes in the expression of muscarinic M1 and M2 cholinergic receptors were assessed in the CA1 and CA3 fields of hippocampus using radioligand binding and autoradiographic techniques with [3H]-pirenzepine and [3H]-AF-DX 116 as ligands. Male Wistar rats of 2 months (young), 12 months (adult) and 27 months (old) of age were examined. Radioligand binding analysis revealed a significant decrease of the density of muscarinic M1 cholinergic receptors with increasing age and no change in muscarinic M2 cholinergic receptors. Autoradiographic evaluation of the number of silver grains developed within the cell body of pyramidal neurons of the CA1 and CA3 fields revealed a decrease of muscarinic M1 cholinergic receptors in the 27-month-old rats in comparison with younger cohorts and no changes in muscarinic M2 cholinergic receptors. These findings suggest that the reduction of muscarinic M1 sites noticed between rats of 2- and 12-months of age using radioligand binding techniques is probably dependent on the loss of hippocampal neurons rather than on the reduction of receptor density per neuron. Our data also indicate that appropriate morphological techniques associated with quantitative analysis may be useful in assessing age-dependent changes in the expression of neurotransmitter receptors by specific neuronal populations. The possible pharmaco-therapeutic relevance of the decreased expression of muscarinic M1 cholinergic receptors by pyramidal neurons of the hippocampus of old rats is discussed
Design, synthesis and muscarinic activity of deoxamuscarine-related derivatives
No full textThe deoxamuscarine analogs 4-6 were synthesized and their biological profiles at muscarinic subtypes were assessed by functional experiments in isolated guinea pig left atria (M2) and ileum (M3), and rabbit vas deferens (M4). The muscarinic receptor potency, affinity and relative efficacy were determined as well and compared to those estimated for deoxamuscarine. The hydroxy group of deoxamuscarine was replaced by an oxime moiety, affording compound 4 that was a full agonist in all functional assay. Beckmann rearrangement of c-4-methyl-3-oxime-r-1-N,N-dimethylaminomethylcyclopentane gave only one of the possible lactam isomers (r-4-(dimethylamino)methyl-c-6-methyl-2-piperidinone) and the corresponding methiodide 5 was a full agonist. Oxime 4 and piperidinone 5 represent useful leads for the design of new muscarinic ligands
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