1,721,087 research outputs found
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
Evaluation of an Agonist Index: Affinity Ratio for Compounds Active on Muscarinic Cholinergic M2 Receptors
No full textA protocol for predicting full agonist, partial agonist, and antagonist profiles of compounds with M2 muscarinic cholinergic receptor activity was developed using radioligand binding assay techniques with [3H]-N-methyl scopolamine (NMS) and [3H]-Oxotremorine-M (Oxo-M) as radioligands. Full muscarinic cholinergic receptor agonists such as muscarine and oxotremorine-M expressed a high agonist index (> 3000 for M1 muscarinic cholinergic receptors and > 900 for M2 muscarinic cholinergic receptor), whereas muscarinic receptor antagonists (selective or non-selective) for different receptor subtypes gave a low (0.5-10) agonist index. Functional studies performed on preparations of guinea-pig ileum and heart were consistent with radioligand binding assay experiments. The above results suggest that similarly as already established for the M1 muscarinic cholinergic receptor subtype, evaluation of the [3H]-NMS/[3H]-Oxo-M ratio may provide useful information on the profile of compounds acting at the M2 muscarinic cholinergic receptor subtype. The availability of simple and predictive techniques for the characterization of muscarinic M2 cholinergic receptor agonists, may help the identification of new compounds in therapeutic areas in which stimulation or inhibition of this receptor is desirabl
Dopamine D-5 receptors: A challenge to medicinal chemists
No full textDue to the lack of highly selective dopamine D1 or D5 receptor ligands, only few data about activation or blocking of these receptor subtypes are available. The present review collects the available information about molecules with notable affinity for D5 receptor subtype with the purpose to help the researchers to design novel D5 selective ligands, whose discovery may enrich the knowledge about the physiological function of such a receptor, provide information about its topography, as well as lead to novel potential therapeutic tool
Synthesis and Structure-Activity Relationship Studies in a Series of 2-Substituted 1,3-Dioxolanes Modified at the Cationic Head.
No full textSynthesis and dopamine receptor affinities of 2-(4-fluoro-3-hydroxyphenyl)ethylamine and N-substituted derivatives
No full textThe synthesis of 2-(4-fluoro-3-hydroxyphenyl)ethylamine (26) and of some N,N-dialkyl derivatives (27-30) starting
from 4-fluoro-3-hydroxytoluenea nd their in vitro binding affinities for dopamine (DA) receptor are reported. The
amine 26 can be regarded as a molecular modification of DA in which the para hydroxyl group is replaced by fluorine. The new compounds 26-30 were evaluated for their affinity at D-1 and D-2 DA receptor subtypes by displacement of [3H]SCH 23390 (D-1 selective) and [3H]spiperone (D-2 selective). The amine 26 had about 2-fold less affinity for D-1 and D-2 binding sites than DA. The substitution of the amino group with ethyl, n-propyl, and 2-phenylethyl groups decreased the affinity for D-1 binding sites but greatly enhanced the effectiveness on D-2 binding sites. The N-ethyl- (28) and N-n-propyl-N-(2-phenylethyl)-2-(4-fluoro-3-hydroxypheny1)ethylam(i3n0e) were the most potent members of the series with high selectivity for D-2 binding sites. A similar effect was observed with isomeric N-n-propyl-N-(2 -phenylethyl)-2-3( -fluoro-4-hydroxypheny1)ethylamine( 31) which was approximately 65 times more selective for D-2 sites vs D-1 sites. The introduction of a 2-phenylethyl group on the nitrogen atom induce the highest effect, perhaps as a consequence of an increased liposolubility or of binding to a complementary lipophilic site on the receptor
Roles of Wnt/β-catenin signalling pathway in the bony repair of injured growth plate cartilage in young rats
No full textGrowth plate cartilage is responsible for longitudinal growth of the long bone in children, and its injury is often repaired by bony tissue, which can cause limb length discrepancy and/or bone angulation deformities.Whilst earlier studies with a rat growth plate injury repair model have identified inflammatory, mesenchymal infiltration, osteogenesis and remodeling responses, the molecular mechanisms involved in the bony repair remain unknown. Since our recent microarray study has strongly suggested involvement of Wnt–β-catenin signalling pathway in regulating the growth plate repair and the pathway is known to play a crucial role in the osteogenic differentiation of mesenchymal progenitor cells, the current study investigated the potential roles of Wnt–β-catenin signalling pathway in the bony repair of injured tibial growth plate in rats. Immunohistochemical analysis of the growth plate injury site revealed β-catenin immunopositive cells within the growth plate injury site. Treatment of the injured rats with the β-catenin inhibitor ICG-001 (oral gavage at 200 mg/kg/day for 8 days, commenced at day 2 post injury) enhanced COL2A1 gene expression (by qRT-PCR) and increased proportion of cartilage tissue (by histological analysis), but decreased level of osterix expression and amount of bone tissue, at the injury site by day 10 post-injury (n=8, P<0.01 compared to vehicle controls). Consistently, in vitro studies with bone marrow stromal cells from normal rats showed that β-catenin inhibitor ICG-001 dose dependently inhibited expression of Wnt target genes Cyclin D1 and survivin (P<0.01). At 25 mM, ICG-001 suppressed osteogenic (by CFU-f-ALP assay) but enhanced chondrogenic (by pellet culture) differentiation. These results suggest that Wnt/β-catenin signalling pathway is involved in regulating growth plate injury repair by promoting osteoblastogenesis, and that intervention of this signalling could represent a potential approach in enhancing cartilage repair after growth plate injury
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
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
Synthesis and antimuscarinic activity of derivatives of 2-substituted-1,3-dioxolanes
No full textGeometric cis, trans isomers, derivatives of 2-substituted-1,3-dioxolanes and 2-substituted-1,3-dioxanes were designed and studied as antimuscarinic agents. The synthesized compounds were evaluated as perchlorides and methiodides by functional tests with rabit vas deferens (putatvie M1), guinea-pig heart (M2) and guinea-pig ileum (M3). The effect of the replacement of a trimethylammonium group with a dimethylsulfonium in the two rings was also evalutated. Pharmacological results indicate that the 1,3-dioxane nucleus shows the highest stereoselective values on the studied receptorsGeometric cis, traits isomers, derivatives of 2-substituted-1,3-dioxolanes and 2-substituted-1,3-dioxanes were designed and studied as antimuscarinic agents. The synthesized compounds were evaluated as perchlorides and methiodides by functional tests with rabbit vas deferens (putative M-1), guinea-pig heart (M-2) and guinea-pig ileum (M-3). The effect of the replacement of a trimethylammonium group with a dimethylsulfonium in the two rings was also evaluated. Pharmacological results indicate that the 1,3-dioxane nucleus shows the highest stereoselective values on the studied receptors
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