958 research outputs found
Might Allyphenyline and Cyclomethyline Become Profitable Multifunctional Tools in the Opioid Addiction Management?
No full textOpioid addiction, termed a “chronic, relapsing disease”, is associated with a myriad of health and social problems and its management is an extremely important area of research. alpha-2-Adrenoreceptors (alpha-2-ARs), belonging to the superfamily of G-protein coupled receptors, have been demonstrated to be extremely sensitive to opioid exposure and to play a key role in opiate withdrawal symptoms. In detoxification alpha-2-AR agonists, such as clonidine and lofexidine, are often clinically used to reduce the intensity of withdrawal symptoms. However, the activation of the alpha-2A-AR subtype, triggered by these compounds, is responsible for evoked sedation and hypotension side effects. Therefore, selective alpha-2C-AR agonists, devoid of the side effects induced by the alpha-2A-AR stimulation, alone or in combination with opioids might represent an improvement over current therapies with clonidine-like drugs. Interestingly, depending on their preferred extended molecular conformation, allyphenyline (1) and its analogue cyclomethyline (2) behave as alpha-2C-AR agonists/alpha-2A-AR antagonists.1 Due to such a biological profile, 12 and 2 prove to be devoid of sedative effect as well as to prevent and contrast morphine dependence at very low dose (0.05 mg/Kg) in mice. Elevate comorbidity between opioid addiction and depression emerges from several clinical studies. It is noteworthy that, unlike the clinically used clonidine, 1 and 2 are able to provide alone and at the same low dose (0.05 mg/Kg) both improvement of morphine withdrawal symptoms and potent antidepressant-like effect. The study of the enantiomers of 1 and 2 highlights that the antidepressant response is associated with an additional 5-HT1A receptor (5-HT1A-R) activation. 1 and 2 display favourable in vitro ADME profiles and negligible activity on the hERG channel
1,4-Dioxane Nucleus as a Suitable Scaffold for the Characterization of Different Receptor Systems\ud
No full textOne of the strategies, which can lead to the discovery of novel biologically active compounds and over the last 20 years has emerged as a fruitful approach, is the identification and use of molecular scaffolds with versatile binding properties. For such structures, bearing appropriate molecular decoration and, therefore, able to\ud
recognize with high affinity more unrelated targets, the term “privileged structure” has been proposed.\ud
In this study it has been demonstrated that the properly substituted 1,4-dioxane nucleus has proven to be a suitable scaffold for:\ud
a) potent muscarinic receptor (mAChRs) agonists and antagonists;\ud
b) selective alpha2A-adrenoreceptor (alpha2A-ARs) antagonists;\ud
c) selective alpha1D-adrenoreceptor (alpha1D-ARs) antagonists;\ud
d) potent 5-HT1A serotoninergic receptor full agonists;\ud
e) potential anticancer agents.\ud
It is well known that the (1,3-dioxolan-4-yl)-N,N,N-trimethylmethanaminium iodide nucleus has been used for many years as a scaffold for its ability to give potent\ud
muscarinic agonists or antagonists, depending on the size of the substituent in position 2 (methyl or bulkier group, respectively). Inspired by this scaffold, I designed, prepared and studied at all five muscarinic receptor subtypes two series of 1,4-dioxane analogues substituted in positions 5 and 6 with methyl or bulkier groups to obtain agonists and antagonists, respectively.\ud
Concerning agonists the most interesting compound was the cis-trimethyl-(6-methyl-1,4-dioxan-2-ylmethyl)-ammonium iodide. Such a compound behaved as a full agonist at M1-M3 subtypes (pD2 = 5.65, 7.57, 7.34, respectively) and as a partial agonist at M4 subtype (pD2 = 5.87).\ud
As expected, the replacement of the methyl group in positions 5 or 6 of the agonist compounds with bulkier aryl or cycloalkyl rings modulated their muscarinic profile\ud
from agonists to antagonists. The most productive modification for affinity was the insertion of two phenyl groups in position 6, such a derivative proving to be a potent antagonist at all muscarinic receptor subtypes.\ud
The biological evaluation of the enantiomers of the most interesting both agonist or antagonist compounds demonstrated that the muscarinic effect was closely related to the stereochemistry of the ligands.\ud
It is well known that the benzodioxane nucleus bearing an appropriate substituent at position 2 can discriminate markedly among alpha-AR adrenoreceptor subtypes. In fact, WB 4101 and Idazoxan, both carrying a 1,4-benzodioxan-2-yl moiety as a basic feature but having a different 2-substituent [(2,6-dimethoxyphenoxy)ethylamine, or\ud
imidazoline] are highly selective for alpha1- and alpha2-ARs, respectively. A variety of their analogues have been studied involving a modification of the dehydrodioxane ring to develop high-affinity, site-selective ligands for each of the three alpha 1- and alpha2-AR subtypes (alpha1a/A, alpha1b/B,B alpha1d/D; alpha2A, alpha2B,B alpha2C). I have expanded on the structure-activity relationship study by investigating the possibility that the quite planar 1,4- benzodioxane privileged structure of WB 4101 and Idazoxan might be replaced by the less conformationally constrained 1,4-dioxane ring. The increased flexibility of 1,4-dioxane moiety might allow a better interaction with alpha-AR subtypes or favour the interaction with only one of them, leading hopefully to selectivity. Therefore, WB 4101- and Idazoxan-related derivatives obtained by inserting one or two phenyl groups in 5 or 6 position of 1,4-dioxane nucleus were designed and studied by binding and functional experiments.\ud
The pharmacological profiles of alpha2-AR antagonists related to Idazoxan were investigated using CHO cell lines stably expressing cDNAs encoding human alpha2A-, alpha2B-, and alpha2C-AR subtypes by cytosensor microphysiometer. Among the new compounds, only trans-2-(5-phenyl-1,4-dioxan-2-yl)-4,5-dihydro-1H-imidazole behaved as a competitive antagonist at alpha2A-AR subtype with a pKb value of 7.14\ud
similar to that of Idazoxan (pKb = 7.73). Interestingly, unlike Idazoxan, this compound was not active at alpha2B-, and alpha2C-AR subtypes. Therefore, for its particular alpha2A selective antagonism, this compound might be of interest for antinociceptive drug development, according to the observation that alpha2A-AR selective antagonists mightincrease the opioid analgesia.\ud
Concerning the alpha1-AR antagonists the replacement of the condensed benzene ring of WB 4101 with two phenyl rings inserted in position 6 of the 1,4-dioxane nucleus,\ud
along with the simultaneous removal of one methoxy group in the 2,6-dimethoxyphenoxy moiety, favoured alpha 1d subtype selectivity. In fact, the alpha1d affinity value (pKi = 8.94) was significantly higher than those for alpha1a and alpha1b subtypes (pKi =7.56 and 7.25, respectively).\ud
Moreover, the WB 4101-related derivatives were also evaluated on HeLa cells, expressing 5-HT1A serotoninergic receptor, since it is well known that this receptor\ud
exhibits a high degree of homology to alpha1-ARs. Among all the 5-phenyl, 6-phenyl and 5,5-diphenyl derivatives the presence of a 2-methoxy substituent in the 2-phenoxyethyl moiety was beneficial for high 5-HT1A affinity. When two phenyl rings were inserted in position 6, the methoxy-substitution in the 2-phenoxyethyl moiety did not seem to affect binding to the 5-HT1A receptor, all three derivatives\ud
(unsubstituted, 2-methoxy- and 2,6-dimethoxy-substituted) showing similar nM affinity values. Interestingly, the 6,6-diphenyl derivative bearing the 2,6- dimethoxyphenoxy moiety, examined in the [35S]GTP_S binding at the human cloned 5-HT1A receptor, was a potent full agonist with a pD2 value of 8.28. It also showed good selectivity for 5-HT1A towards the alpha1A-, alpha1B- and alpha1D-AR subtypes, representing a new lead in the design of potent full 5-HT1A agonists significantly selective over alpha1-ARs.\ud
Moreover, following our recent observation that alpha1D- and alpha1B-ARs are expressed in PC-3 prostate cancer cells and are involved in the modulation of apoptosis and cell proliferation, the cytotoxic effects of the new compounds on this cell line were determined. The 6,6-diphenyl derivative unsubstituted in the 2,6-dimethoxyphenoxy\ud
moiety exhibited the highest potency in inhibiting PC-3 cell growth and seemed to activate a mitochondrial-independent apoptotic pathway.\ud
In conclusion, the results obtained in my research proved the ability of the 1,4-dioxane nucleus to act as a versatile biological scaffold
Topic Review:: Levodopa/Receptor Ligands in Parkinson’s Disease
No full textLevodopa (LD) is the most effective drug in the treatment of Parkinson’s disease (PD). However, although it represents the “gold standard” of PD therapy, LD can cause side effects, including gastrointestinal and cardiovascular symptoms as well as transient elevated liver enzyme levels. Moreover, LD therapy leads to LD-induced dyskinesia (LID), a disabling motor complication that represents a major challenge for the clinical neurologist. Due to the many limitations associated with LD therapeutic use, other dopaminergic and non-dopaminergic receptor drugs, including serotoninergic, gluamatergic and noradrenergic receptor ligands, are being developed to optimize the treatment response
Farmaci attivi sul sistema nervoso adrenergico
No full textAttraverso uno stile leggibile e accattivante, il testo offre una comprensione esaustiva delle fasi di progettazione dei farmaci e dei meccanismi molecolari attraverso cui un farmaco esercita la sua azione all'interno di un organismo. Il libro rappresenta un'opera con l'ambizione di diventare un punto di riferimento nell'insegnamento della Chimica farmaceutica in Italia. Il testo sottolinea l'importanza della Chimica farmaceutica nelle nostre vite, evidenziando il fascino di una disciplina che integra chimica, biochimica, fisiologia, microbiologia, biologia cellulare e farmacologia. Sarà quindi di grande interesse per tutti quegli studenti che aspirano a una carriera futura nell'industria farmaceutica
Effects of imidazoline I2 receptor ligands on acute nociception in rats
No full textThis study examined the antinociceptive effects of seven imidazoline I 2 receptor ligands in a rat warm water tail withdrawal procedure (46 and 50°C). Agmatine, 2-BFI, phenyzoline, and diphenyzoline produced a significant antinociceptive activity at 46°C. BU224, S22687, and idazoxan had no effect at 46°C up to doses that altered the locomotor activity. None of the drugs showed antinociceptive activity at 50°C. It is suggested that I 2 receptor agonists have antinociceptive activity for acute phasic pain under weak noxious stimulus, and the effects are efficacy-dependent. These data explain the findings that I 2 receptor agonists enhance the antinociceptive effects of opioids and support developing higher-efficacy I 2 receptor agonists for the treatment of pain
From benzodioxane to 1,4-dioxane scaffold in the design of 5-HT1A serotoninergic full agonists from α1-adrenergic antagonists
No full textThe quite planar 1,4-benzodioxane structure of the non-subtype selective α1-adrenergic antagonist WB 4101 (1) [1] has successfully been replaced by the less conformationally
constrained 1,4-dioxane nucleus substituted in its positions 5 or 6 with one or two pendant phenyl rings. Indeed, the compounds characterized by N-(6,6-diphenyl-1,4dioxan-2ylmethyl)-2-phenoxyethanamine structure, where R is 2,6-OCH3 (2), 2-OCH3 (3), or H (4), showed full 5-HT1A receptor agonism, selective α1D-adrenergic antagonism or significant cytotoxic activity, respectively [2]. Considering that a high degree of homology exits between 5-HT1A and α1-adrenergic receptors [3] and WB 4101 itself displays 5-HT1A affinity, the improved 5-HT1A/α1-adrenergic profile of compound 2 appeared noteworthy. Therefore, to identify stereochemical requirements for the selective recognition of the above mentioned biological targets, the derivatives 2-4 have been resolved into the corresponding enantiomers. In addition, novel ligands, bearing one or two phenyl groups in positions 2 or 3 of the 1,4-dioxane scaffold, have been prepared and studied.
References
[1]. Mottram, D. R.; Kapur, H. J. Pharm. Pharmacol., 27, 295-296, 1975.
[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. J. Med. Chem., 51, 6359-6370, 2008.
[3]. Trumpp-Kallmeyer, S.; Hoflack, J.; Bruinvels, A.; Hibert, M. J. Med. Chem., 35, 3448-3462, 1992
Topic review: Zinc Complexes as Anticancer Agents
No full textThe search for anticancer metal-based drugs alternative to platinum derivatives could not exclude zinc derivatives due to the importance of this metal for the correct functioning of the human body. Zinc, the second most abundant trace element in the human body, is one of the most important micro-elements essential for human physiology. Its ubiquity in thousands of proteins and enzymes is related to its chemical features, in particular, its lack of redox activity and its ability to support different coordination geometries and to promote fast ligands exchange. Analogously to other trace elements, the impairment of its homeostasis can lead to various diseases and in some cases can be also related to cancer development. However, zinc complexes generally exert lower toxicity in comparison to other metal-based drugs and many zinc derivatives have been proposed as antitumor agents. Among them, zinc complexes comprising N-donor ligands have been surveyed and analyzed
Fabio Luca Cavazza, la nascita del centro-sinistra e la "nuova frontiera"
No full textStudio sulla figura di Fabio Luca Cavazza e sulla sua attività, prima come co-fondatore di il Mulino, poi come mediatore tra il nascente centrosinistra italiano e il partito democratico statunitens
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
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