1,721,063 research outputs found
Receptor drug interaction: europium employment for studying the biochemical pathway of GPRC activation
No full textExploring prospects of β3-adrenoceptor agonists and inverse agonists for colon motility control
No full textInverse agonists are useful active ingredient of drugs clinically used to treat diseases mainly involving receptors endowed with nonendogenous
agonist induced activity (constitutive
or basal activity). SP-1e and SP-1g are the first two potent and highly selective β3-adrenoceptor
inverse agonists [EC50=181 nM (IA=-
64%) and 136 nM (IA=-73%), respectively], which their peculiar activity seems due to the absolute configurations of the two stereogenic
centres present in each molecule. Rat proximal colon motility measurements allowed their further pharmacological characterization and pA2 values determination by Schild analysis (7.89
and 8.16, respectively). The purpose of our work is a further characterization of our novel β3-adrenoceptor agonists (SP-1a-d, SP-1f,1h) and inverse agonists (SP-1e and SP1g) on rat
proximal colon motility and a confirmation of their inverse agonist nature in a more complex
system like the functional test on rat proximal colon. Male Wistar rats segment of the proximal colon were placed in organ baths containing
Krebs solution. Muscle tension was recorded isotonically. Cumulative β3-AR agonists doses experiments were performed for each test compound: isoprenaline, BRL37344, SP-1a-d, SP-1f and SP-1h were dissolved in Krebs. The EC50 values of each agonists and
pA2 of inverse agonists were determined. SP-1a-d, SP-1f and SP-1h in rat colon have a muscle
relaxing effect thus confirming their partial agonist activity found in CHO-K1 cell line. SP-1e and SP-1g behaved as antagonists with pA2 values of 7.89 and 8.16, espectively. In conclusion, experiments carried out by using
isolated rat proximal colon allowed us to determine the pA2 values of the two β3-AR inverse agonists and add knowledge on the behavior of a novel set of compounds and their possible value as agents useful whenever is necessary to also control the colon motility
Biomarkers for the early diagnosis of Alzheimer’s disease: the challenge of XXI century.
No full textZervimesine, a Small Sigma-2 Receptor Selective Modulator for Alzheimer’s Disease
No full textZervimesine is a small molecule, able to cross the blood−brain barrier,
readily available by straightforward organic chemistry processes, showing few “off-target” effects, but displays a potent and selective S2R modulator profile. Evidence suggests Zervimesine can protect synapses and neurons by preventing the toxic effects of soluble Aβ oligomers
The Pivotal Role of Copper in Neurodegeneration: A New Strategy for the Therapy of Neurodegenerative Disorders
Full text linkCopper is an essential trace element for the human body since it is a cofactor of several enzymes and proteins and plays a pivotal role in several biological functions (e.g., respiration, protection from oxidative damage, iron metabolism, etc.), also including the central nervous system development and functioning (e.g., synthesis of neurotransmitters, myelination, activation of neuropeptides, etc.). Therefore, copper dysmetabolism is associated with different toxic effects, mainly represented by oxidative stress, and it has been reported in many neurodegenerative disorders, such as Wilson's disease, Menkes disease, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This paper shows a detailed report of how copper is involved in the pathophysiology of these diseases. Moreover, a hint on novel therapeutic approaches based on restoring copper homeostasis through metal chelators will be pointed out
Potent and selective tariquidar bioisosters as potential PET radiotracers for imaging P-gp
No full textCompounds 8a–d have been designed as bioisosters of tariquidar for imaging P-gp expression and density
by PET. The results displayed that compounds 8b and 8d could be considered potential P-gp/BCRP ligands
suitable as 11C and 18F radiotracers, respectively
In vitro and ex vivo characterization of sigma-1 and sigma-2 receptors: agonists and antagonists in biological assays
No full textMethods for addressing sigma receptor affinity and activity have been explored and although several protocols have been employed, only few procedures resulted reliable. Sigma-1 receptor affinity protocol using guinea-pig brain and (+)-[(3)H]-pentazocine and sigma-2 receptor affinity protocol employing rat liver and [(3)H]-DTG are usually reported by authors as standard procedures. By contrast, the intrinsic activity evaluation of sigma ligands has been performed in several manners: tumor cell lines, isolated organ bath, in vivo animal model. The last is not considered in the present paper because this method studied the physiological role of sigma receptors. The studies carried out in tumor cell lines involved the role of sigma receptors in tumors progression while, although isolated organ bath experiment employed physiological samples, the pharmacokinetic properties of ligands, a strictly requirement for the in vivo assays, did not affect the pharmacodynamic properties of tested compounds. The advances in the above mentioned assays have been reported
Effect of some P-glycoprotein modulators on Rhodamine-123 absorption in guinea-pig ileum
No full textSeveral reference compounds such as Cyclosporin A, Tamoxifen, Verapamil, and our compound 1, known as P-gp modulators, have been tested for their P-gp modulating activity in isolated organ bath. Compound 1 showed the best result in organ bath experiment (EC(50)=14.7 microM), Cyclosporin A and Tamoxifen displayed EC(50)=25.2 and 39.4 microM, respectively
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