Papers by Serena Pasquini
Frontiers in psychiatry, 2010
The present study was designed to evaluate (a) alcohol self-administration behavior of selectivel... more The present study was designed to evaluate (a) alcohol self-administration behavior of selectively bred, Sardinian alcohol-preferring (sP) rats exposed to the so-called "sipper" procedure (characterized by the temporal separation between alcohol-seeking and -taking phases), and (b) the effect of the positive allosteric modulator of the GABA(B) receptor, GS39783, on alcohol self-administration in sP rats exposed to this procedure. To this end, sP rats were initially trained to lever-respond under a reinforcement requirement (RR) 55 (RR55) for alcohol. Achievement of RR55 resulted in the 20-min presentation of the alcohol (15%, v/v)-containing sipper bottle. Once stable levels of lever-responding and alcohol consumption were reached, rats were treated with 0, 25, 50, and 100 mg/kg GS39783 (i.g.) 60 min before the self-administration session. Rats displayed robust alcohol-seeking (as suggested by relatively short latencies to the first lever-response and high frequencies of l...
Frontiers in Psychiatry, 2011
Recent studies demonstrated that activation of the GABA B receptor, either by means of orthosteri... more Recent studies demonstrated that activation of the GABA B receptor, either by means of orthosteric agonists or positive allosteric modulators (PAMs), inhibited different nicotinerelated behaviors, including intravenous self-administration and conditioned place preference, in rodents. The present study investigated whether the anti-nicotine effects of the GABA B receptor agonist, baclofen, and GABA B PAMs, CGP7930, and GS39783, extend to nicotine stimulant effects. To this end, CD1 mice were initially treated with baclofen (0, 1.25, and 2.5 mg/kg, i.p.), CGP7930 (0, 25, and 50 mg/kg, i.g.), or GS39783 (0, 25, and 50 mg/kg, i.g.), then treated with nicotine (0 and 0.05 mg/kg, s.c.), and finally exposed to an automated apparatus for recording of locomotor activity. Pretreatment with doses of baclofen, CGP7930, or GS39783 that did not alter locomotor activity when given with nicotine vehicle fully prevented hyperlocomotion induced by 0.05 mg/kg nicotine. These data extend to nicotine stimulant effects the capacity of baclofen and GABA B PAMs to block the reinforcing, motivational, and rewarding properties of nicotine. These data strengthen the hypothesis that activation of the GABA B receptor may represent a potentially useful, anti-smoking therapeutic strategy.
Tuberculosis, 2013
A set of 21 new fluoroquinolones bearing an aromatic or heteroaromatic moiety at C-7 and an alkyl... more A set of 21 new fluoroquinolones bearing an aromatic or heteroaromatic moiety at C-7 and an alkyl group at N-1 were synthesized based on the lead structure of pirfloxacin and tested in vitro against Mycobacterium tuberculosis (M. tuberculosis) H37Rv by MIC determination in liquid medium. Among the synthesized compounds, 1-(tert-butyl)-6-fluoro-7-(4-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3carboxylic acid (2o) and 1-(tert-butyl)-6-fluoro-7-(pyridin-3-yl)-4-oxo-1,4-dihydroquinoline-3carboxylic acid (2n) were found to be the most active ones against M. tuberculosis H37Rv with the same MICs of reference compounds ciprofloxacin (CFX) and levofloxacin (LFX). MICs of 2o and 2n were determined for fluoroquinolone-sensitive and fluoroquinolone-resistant M. tuberculosis clinical isolates and 2o was the most active compound with up 4-fold difference of MIC with respect to CFX. The activity of 2o was also tested at the concentration of 16 mg/mL against M. tuberculosis H37Rv in infected murine macrophages. The results showed a 4-fold decrease in viable count of cell-associated mycobacteria with respect to untreated controls after 48 h of drug incubation.
Pharmacological Research, 2012
Cannabinoid CB2 receptor activation has been shown to have many pharmacological but not psychotro... more Cannabinoid CB2 receptor activation has been shown to have many pharmacological but not psychotropic effects. The aim of this study was to investigate the potential protection of brain tissues afforded by the novel substituted 4-quinolone-3-carboxylic acid derivative COR167, a selective CB2 agonist, toward ischemia and reperfusion-induced injury, as well as the mechanism of this potential effect. Rat brain cortical slices subjected to oxygen and glucose deprivation (OGD) followed by re-oxygenation were used. Cell damage was quantified by measuring at the end of the reperfusion phase the release into the artificial cerebrospinal fluid (ACSF) of lactate dehydrogenase (LDH), glutamate, IL-6 and TNF-␣ and by evaluating in tissue the lipid-peroxides (thiobarbituric acid-reactive substances, TBARS), the free, reduced glutathione content (GSH) and the water gain (TWG), taken as an index of cell swelling. COR167 (10 nM or 100 nM), added to ACSF during the entire reperfusion phase, markedly reduced LDH and glutamate release, as well as TWG. Lower (0.1-1 nM) or higher concentrations (1000 nM) were ineffective, suggesting thereby an hormetic behavior. COR167 at 10 nM concentration markedly reverted in tissues TBARS increase and GSH decrease, while reducing IL-6 and TNF-␣ release into ACSF. COR167 effects on glutamate and LDH release were abrogated by the selective CB2 inverse-agonists COR170 (1 nM) and AM630 (1 M) but not by the CB1 antagonist AM251 (1 M). COR170 as well as AM630 per se were able to revert TWG. The CB2 receptor agonist COR167 potently protected rat brain cortical slices against OGD and reperfusion injury, partly through CB2 receptors activation.
Journal of Pharmacology and Experimental Therapeutics, 2011
The potential efficacy of GABA B receptor agonists in the treatment of pain, drug addiction, epil... more The potential efficacy of GABA B receptor agonists in the treatment of pain, drug addiction, epilepsy, cognitive dysfunctions, and anxiety disorders is supported by extensive preclinical and clinical evidence. However, the numerous side effects produced by the GABA B receptor agonist baclofen considerably limit the therapeutic use of this compound. The identification of positive allosteric modulators (PAMs) of the GABA B receptor may constitute a novel approach in the pharmacological manipulation of the GABA B receptor, leading to fewer side effects. The present study reports the identification of two novel compounds, methyl 2-(1-adamantanecarboxamido)-4-ethyl-5methylthiophene-3-carboxylate (COR627) and methyl 2-(cyclohexanecarboxamido)-4-ethyl-5-methylthiophene-3-carboxylate (COR628), which act as GABA B PAMs in 1) rat cortical membranes and 2) in vivo assay. Both compounds potentiated GABA-and baclofen-stimulated guanosine 5Ј-O-(3-[ 35 S]thio)-triphosphate binding to native GABA B receptors, while producing no effect when given alone. GABA concentration-response curves in the presence of fixed concentrations of COR627 and COR628 revealed an increase of potency of GABA rather than its maximal efficacy. In radioligand binding experiments [displacement of the GABA B receptor antagonist, 3-N-[1-((S)-3,4dichlorophenyl)-ethylaminol]-2-(S)hydroxypropyl cyclo-hexylmethyl phosphinic acid ([ 3 H]CGP54626)], both COR627 and COR628 increased the affinity of high-and low-affinity binding sites for GABA, producing no effect when administered alone up to a concentration of 1 mM. In vivo experiments indicated that pretreatment with per se ineffective doses of COR627 and COR628 potentiated the sedative/hypnotic effect of baclofen. In conclusion, COR627 and COR628 may represent two additional tools for use in investigating the roles and functions of positive allosteric modulatory binding sites of the GABA B receptor.
Journal of Medicinal Chemistry, 2009
Bearing in mind the pharmacophoric requirements of both (-)-trans-Delta(9)-tetrahydrocannabinol (... more Bearing in mind the pharmacophoric requirements of both (-)-trans-Delta(9)-tetrahydrocannabinol (THC) and anandamide (AEA), we designed a novel pharmacophore consisting of both a rigid aromatic backbone and a flexible chain with the aim to develop a series of stable and potent ligands of cannabinoid receptors. In this paper we report the synthesis, docking studies, and structure-activity relationships of new resorcinol-anandamide "hybrids" differing in the side chain group. Compounds bearing a 2-methyloctan-2-yl group at position 5 showed a significantly higher affinity for cannabinoid (CB) receptors, in particular when an alkyloxy chain of 7 or 10 carbon atoms was also present at position 1. Derivative 32 was a potent CB(1) and CB(2) ligand, with K(i) values similar to that of WIN 55-212 and potent antinociceptive activity in vivo. Moreover, derivative 38, although less potent, proved to be the most selective ligand for CB(2) receptor (K(i)(CB(1)) = 1 muM, K(i)(CB(2)) = 35 nM).
Current Medicinal Chemistry, 2012
Bioisosterism is widely used in medicinal chemistry as an approach aimed at either rationally mod... more Bioisosterism is widely used in medicinal chemistry as an approach aimed at either rationally modifying a hit compound into a more potent and/or selective molecule or a lead compound into a more drug-like one. Two different cannabinoid receptors have been cloned from mammalian tissues, the CB1 receptor, mostly expressed in brain, and the CB2 receptor, mostly expressed in the immune system, both regulating a variety of physiological functions. Synthetic cannabinoids have been developed that act as highly selective agonists or antagonists/inverse agonists at one or other of these receptor types with the ultimate goal of modulating the endocannabinoid system. This review takes into account the use of the bioisosteric substitution in the field of cannabinoid ligands as a tool for improving both their pharmacodynamic and pharmacokinetic properties.
Alcoholism: Clinical and Experimental Research, 2012
Background-Administration of the GABA B receptor agonist, baclofen, and positive allosteric modul... more Background-Administration of the GABA B receptor agonist, baclofen, and positive allosteric modulator (PAM), GS39783, has been repeatedly reported to suppress multiple alcohol-related behaviors, including operant oral alcohol self-administration, in rats. The present study was designed to compare the effect of baclofen and GS39783 on alcohol self-administration in three lines of selectively bred, alcohol-preferring rats: Indiana alcohol-preferring (P), Sardinian alcoholpreferring (sP), and Alko Alcohol (AA). Methods-Rats of each line were initially trained to respond on a lever, on a fixed ratio (FR) 4 (FR4) schedule of reinforcement, to orally self-administer alcohol (15%, v/v) in daily 30-min sessions. Once responding reached stable levels, rats were exposed to a sequence of experiments testing baclofen (0, 1, 1.7, and 3 mg/kg; i.p.) and GS39783 (0, 25, 50, and 100 mg/kg; i.g.) on FR4 and progressive ratio (PR) schedules of reinforcement. Finally, to assess the specificity of baclofen and GS39783 action, rats were slightly food-deprived and trained to lever-respond for food pellets. Results-The rank of order of the reinforcing and motivational properties of alcohol was: P>sP>AA rats. Under both FR and PR schedules of reinforcement, the rank of order of potency and efficacy of baclofen and GS39783 in suppressing alcohol self-administration was: P>sP>AA rats. Only the highest dose of baclofen reduced lever-responding for food pellets; this effect was common to all three rat lines. Conversely, no dose of GS39783 altered lever-responding for food in any rat line. Conclusions-These results suggest that: (a) the strength of the reinforcing and motivational properties of alcohol differ among P, sP, and AA rats; (b) the reinforcing and motivational properties of alcohol in P, sP, and AA rats are differentially sensitive to treatment with baclofen and GS39783; (c) the heterogeneity in sensitivity to baclofen and GS39783 of alcohol selfadministration in P, sP, and AA rats may resemble the differential effectiveness of
Journal of Combinatorial Chemistry, 2009
ChemMedChem, 2012
Three heterocyclic systems were selected as potential surrogates of the amide linker for a series... more Three heterocyclic systems were selected as potential surrogates of the amide linker for a series of 1,6-disubstituted-4-quinolone-3-carboxamides, potent and selective CB2 ligands exhibiting scarce water solubility, with the aim of improving their physicochemical profile and also of clarifying properties of importance for amide bond mimicry. Among the newly synthesized compounds, the 1,2,3-triazole derivative 11 emerged as the most promising in terms of both physicochemical and pharmacodynamic properties. When assayed in vitro, 11 exhibited inverse agonist activity, whereas, in vivo, in the formalin test in mice, it produced analgesic effects antagonized by a well established inverse agonist. Metabolic studies allowed the identification of the side chain hydroxylated derivative 32 as its only metabolite which, in its racemic form, showed still appreciable CB2 selectivity, but was 150-fold less potent than the parent compound.
Journal of medicinal chemistry, Jan 14, 2012
In our search for new cannabinoid receptor modulators, we describe herein the design and synthesi... more In our search for new cannabinoid receptor modulators, we describe herein the design and synthesis of three sets of indole-based ligands characterized by an acetamide, oxalylamide, or carboxamide chain, respectively. Most of the compounds showed affinity for CB2 receptors in the nanomolar range, with K(i) values spanning 3 orders of magnitude (377-0.37 nM), and moderate to good selectivity over CB1 receptors. Their in vitro functional activity as inverse agonists was confirmed in vivo in the formalin test of acute peripheral and inflammatory pain in mice, in which compounds 10a and 11e proved to be able to reverse the effect of the CB2 selective agonist COR167.
European Journal of Medicinal Chemistry, 2000
New 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides were synthesized as cannabinoid (CB) rec... more New 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides were synthesized as cannabinoid (CB) receptor ligands. Compound 11 (CB1Ki=2.3nM, CB1 SI=163.6) showed CB1 receptor affinity and selectivity superior to Rimonabant and AM251. Acute administration of 2mg/kg 11 reduced sucrose, but not regular food, intake in rats. On the other hand, compound 23 (CB2Ki=0.51nM, CB2 SI=30.0) showed significant affinity and selectivity for the CB2 receptor. The results presented
Tetrahedron, 2008
The development of a straightforward synthesis of 4-amino-6-benzyl-6H-pyrrolo[3,4-d]pyrimidine an... more The development of a straightforward synthesis of 4-amino-6-benzyl-6H-pyrrolo[3,4-d]pyrimidine and 7-amino-2-benzyl-2H-pyrazolo[4,3-d]pyrimidine derivatives allowed for the preparation of a small family of potential Hsp90 inhibitors. Some of the newly synthesized compounds showed Hsp90 inhibitory activity in preliminary biological assays.
Tetrahedron, 2011
A practical and general synthesis of 1,3,6-trisubstituted quinolin-4(1H)-ones starting from 1-alk... more A practical and general synthesis of 1,3,6-trisubstituted quinolin-4(1H)-ones starting from 1-alkyl-6bromo-3-iodoquinolin-4(1H)-one is described, based on regioselective sequential palladium-catalyzed cross-coupling reactions, namely SuzukieMiyaura, Sonogashira and aminocarbonylation reactions, under microwave irradiation. Good substrate generality, ease of execution and practicability make this method exploitable for the generation of libraries of chemically diverse 4-quinolones.
Journal of Medicinal Chemistry, 2008
The new 1-phenyl-5-(1H-pyrrol-1-yl)pyrazole-3-carboxamides were compared with the reference compo... more The new 1-phenyl-5-(1H-pyrrol-1-yl)pyrazole-3-carboxamides were compared with the reference compounds AM251 and SR144528 for cannabinoid hCB 1 and hCB 2 receptor affinity. Compounds bearing 2,4dichlorophenyl or 2,4-difluorophenyl groups at position 1 and 2,5-dimethylpyrrole moiety at position 5 of the pyrazole nucleus were generally more selective for hCB 1 . On the other hand, the N-cyclohexyl group at the 3-carboxamide was the determinant for the hCB 2 selectivity, in particular when a 3,4-dichlorophenyl group was also present at position 1. Compound 26 was the most selective ligand for the hCB 1 receptor (K i (CB 2 )/K i (CB 1 ) ) 140.7). Derivative 30, the most potent hCB 1 ligand (K i ) 5.6 nM), was equipotent to AM251 and behaved as an inverse agonist in the cAMP assay (EC 50 ∼1 nM). The carbonyl oxygen of both 26 and 30 formed a H-bond with K3.28(192), while the substituents at the nitrogen fitted in a pocket formed by lipophilic residues. This H-bonding interaction was proposed to account for the high affinity for receptors' inactive state and the inverse agonist activity.
Journal of Medicinal Chemistry, 2009
Bearing in mind the pharmacophoric requirements of both (-)-trans-Delta(9)-tetrahydrocannabinol (... more Bearing in mind the pharmacophoric requirements of both (-)-trans-Delta(9)-tetrahydrocannabinol (THC) and anandamide (AEA), we designed a novel pharmacophore consisting of both a rigid aromatic backbone and a flexible chain with the aim to develop a series of stable and potent ligands of cannabinoid receptors. In this paper we report the synthesis, docking studies, and structure-activity relationships of new resorcinol-anandamide "hybrids" differing in the side chain group. Compounds bearing a 2-methyloctan-2-yl group at position 5 showed a significantly higher affinity for cannabinoid (CB) receptors, in particular when an alkyloxy chain of 7 or 10 carbon atoms was also present at position 1. Derivative 32 was a potent CB(1) and CB(2) ligand, with K(i) values similar to that of WIN 55-212 and potent antinociceptive activity in vivo. Moreover, derivative 38, although less potent, proved to be the most selective ligand for CB(2) receptor (K(i)(CB(1)) = 1 muM, K(i)(CB(2)) = 35 nM).
European Journal of Medicinal Chemistry, 2011
European Journal of Medicinal Chemistry, 2010
A series of N-alkyl 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides were synthesized as new ... more A series of N-alkyl 1-aryl-5-(1H-pyrrol-1-yl)-1H-pyrazole-3-carboxamides were synthesized as new ligands of the human recombinant receptor hCB 1 . n-Alkyl carboxamides brought out different SARs from the branched subgroup. Unsubstituted pyrrole derivatives bearing a tert-alkyl chain at the 3-carboxamide nitrogen showed greater hCB 1 receptor affinity than the corresponding unbranched compounds. In particular, the tert-butyl group as a chain terminal moiety strongly improved hCB 1 receptor affinity (compound 24: K i ¼ 45.6 nM; 29: K i ¼ 37.5 nM). Acute administration of either compound 12 or 29 resulted in a specific, dose-dependent reduction in food intake in rats. Such results provide an useful basis for the design of new CB 1 ligands.
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Papers by Serena Pasquini