1,721,046 research outputs found
Adrenoceptors as targets in drug discovery: Medicinal chemistry and therapeutical potential
No full textNo abstrac
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
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
Synthesis and Structure-Activity Relationship Studies in a Series of 2-Substituted 1,3-Dioxolanes Modified at the Cationic Head.
No full textStructural motives of imidazoline molecules favouring the serotonin 5-HT1A receptor activation
No full textFor several years our studies have been engaged in the design and preparation of biologically active ligands directed to different biological systems and characterized by a common scaffold bearing the 2-substituted imidazoline nucleus. We have demonstrated that minor chemical modifications in the bridge (X) determine preferential or multitarget recognition, whereas those in the aromatic moiety are generally responsible for the ligand functional behaviour. Among the most interesting compounds, we point out the nicotinic agonist homoazanicotine, the pheripheral monoamino oxydase A inhibitor amifuraline, the selective I1-imdazoline receptor agonist and antihypertensive agent carbomethyline, the selective I2 imidazoline binding sites ligand phenyzoline, the preferential α2C adrenergic agonist, also endowed with analgesic activity, biphenyline, and the very interesting α2C-AR agonists/α2A-AR antagonists allyphenyline and cyclomethyline. These latter enhance morphine analgesia at low dose (0.05 mg/Kg), preventing and reversing morphine tolerance and dependence without sedative side effects. Such beneficial effects prove to be associated to significant antidepressant effect at the same low dose. Experiments carried out in the presence of the α2-AR antagonist yohimbine and the serotonin 5-HT1A-receptor (5-HT1A-R) antagonist WAY100135 suggest that not only α2C but also 5-HT1A activation is involved in the antidepressant-like activity. In addition, at the same low dose, allyphenyline reduces hyperanxiety-like
behaviour after alcohol intoxication. Therefore, for the first time we have showed that ligands bearing the 2-substituted imidazoline nucleus as a structural motif are also suitable to interact with 5-HT1A-R. With the aim to report further ligands targeting such a receptor and highlight the structural characteristics of our pharmacophore
favouring the 5-HT1A interaction and activation we examined the in vitro 5-HT1A profile of a large number of imidazoline molecules prepared by us over the years. Some novel ligands have also been included in this study. Confirming the versatility of the 2-substituted imidazoline nucleus, the obtained results also suggest that the bridge, bearing a polar function and an additional methyl group, and the aromatic moiety, bearing an ortho substituent of suitable steric hindrance, positively affect the 5-HT1A-R recognition and activation. In addition, both the size and shape of the ortho substituent also appear to govern the behaviour of the chiral compounds. All the aforementioned evidences are further proved by docking and molecular dynamics carried out on a model built by comparative building based on the 5-HT1B receptor X-ray data. Interestingly, and as expected, this investigation has allowed to highlight some potential multifunctional agents able to reduce neuropatic pain, opiate withdrawal syndrome and psychiatric comorbidities
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
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
Structure-Activity Relationships in 1,4-Benzodioxan-Related Compounds. 6. Role of the Dioxane Unit on Selectivity for Alpha1-Adrenoreceptor Subtypes
No full textWB 4101-related benzodioxans 3-9 were synthesized, and their biological profiles at alpha1-adrenoreceptor subtypes and 5-HT1A serotoninergic receptors were assessed by binding assays in CHO and HeLa cells membranes expressing the human cloned receptors. Furthermore, receptor selectivity of selected benzodioxan derivatives was further determined in functional experiments in isolated rat vas deferens (alpha1A) and aorta (alpha1D) and guinea pig spleen (alpha1B), in
additional receptor binding assays in rat cortex membranes containing alpha2-adrenoreceptors and 5-HT2 serotoninergic receptors, and in rat striatum membranes containing D2 dopaminergic receptors. An analysis of the results of receptor binding experiments for benzodioxan-modified derivatives 3-9 showed high affinity and selectivity toward the alpha1a-adrenoreceptor subtype for compounds 3-5 and 7 and a reversed selectivity profile for 9, which was a selective alpha1d antagonist. Furthermore, the majority of structural modifications performed on the prototype 1 (WB 4101) led to a marked decrease in the affinity for 5-HT1A serotoninergic receptors, which may have relevance in the design of selective alpha1A-adrenoreceptor antagonists. The exception
to these findings was the chromene derivative 8, which exhibited a 5-HT1A partial agonist profile
Structure-activity relationship at alpha-adrenergic receptors within a series of imidazoline analogues of cirazoline
No full textSeveral analogues of cirazoline (2), a selective alpha1-adrenoreceptor agonist, were prepared and their pharmacological profiles studied. Although at the alpha1-adrenoreceptor all the compounds displayed a significant agonist activity, at the alpha2-adrenoreceptor they showed either agonist or antagonist activity depending on the nature of the phenyl substituent. The qualitative structure-activity relationship led us to the conclusion that the oxygen atom in the side-chain is essential for alpha1-agonist activity, while the cyclopropyl ring is not, and may be replaced by several groups. Of the groups studied, isopropoxy appears to be the best. Instead, the same substitution (i.e., isopropoxy for the cyclopropyl ring) at alpha2-adrenoreceptors causes a reversal of activity. On the other hand, the cyclopropyl ring seems to be important for alpha1-selectivity. Compound 20 is the most potent alpha1-agonist of the series, being equiactive with cirazoline on rat vas deferens and in pithed rat
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