Synthesis of pyrazolo[1,5-a]pyrimidine ring as a possible bioisosteric replacement of the 5-(1H-pyrrol-1-yl)pyrazole scaffold

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Reduction by the Positive Allosteric Modulator of the GABAB Receptor, GS39783, of Alcohol Self-Administration in Sardinian Alcohol-Preferring Rats Exposed to the “Sipper” Procedure

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 GABAB 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 lever-responding) and -taking (as suggested by alcohol intakes averaging approximately 1.5 g/kg) behaviors. Pretreatment with GS39783 inhibited both alcohol-seeking (the number of rats achieving RR55 and the mean RR value were virtually halved) and -taking (the amount of self-administered alcohol was reduced by approximately 60%). The results of the present study suggest the power of the “sipper” procedure in triggering high levels of alcohol-seeking and -taking behavior in sP rats. Further, these results extend to this additional procedure of alcohol self-administration the capacity of GS39783 to reduce the motivational properties of alcohol and alcohol consumption in sP rats

Activation of the GABAB Receptor Prevents Nicotine-Induced Locomotor Stimulation in Mice

Recent studies demonstrated that activation of the GABAB receptor, either by means of orthosteric agonists or positive allosteric modulators (PAMs), inhibited different nicotine-related behaviors, including intravenous self-administration and conditioned place preference, in rodents. The present study investigated whether the anti-nicotine effects of the GABAB receptor agonist, baclofen, and GABAB 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 GABAB PAMs to block the reinforcing, motivational, and rewarding properties of nicotine. These data strengthen the hypothesis that activation of the GABAB receptor may represent a potentially useful, anti-smoking therapeutic strategy

Optimization of Pyrazole Compounds as Antibiotic Adjuvants Active against Colistin- and Carbapenem-Resistant Acinetobacter baumannii

The diffusion of antibiotic-resistant, Gram-negative, opportunistic pathogens, an increasingly important global public health issue, causes a significant socioeconomic burden. Acinetobacter baumannii isolates, despite causing a lower number of infections than Enterobacterales, often show multidrug-resistant phenotypes. Carbapenem resistance is also rather common, prompting the WHO to include carbapenem-resistant A. baumannii as a "critical priority" for the discovery and development of new antibacterial agents. In a previous work, we identified several series of compounds showing either direct-acting or synergistic activity against relevant Gram-negative species, including A. baumannii. Among these, two pyrazole compounds, despite being devoid of any direct-acting activity, showed remarkable synergistic activity in the presence of a subinhibitory concentration of colistin on K. pneumoniae and A. baumannii and served as a starting point for the synthesis of new analogues. In this work, a new series of 47 pyrazole compounds was synthesized. Some compounds showed significant direct-acting antibacterial activity on Gram-positive organisms. Furthermore, an evaluation of their activity as potential antibiotic adjuvants allowed for the identification of two highly active compounds on MDR Acinetobacter baumannii, including colistin-resistant isolates. This work confirms the interest in pyrazole amides as a starting point for the optimization of synergistic antibacterial compounds active on antibiotic-resistant, Gram-negative pathogens

Has a “Chemical Magic” Opened up New Prospects for Glaucoma?

Chemical modification of the prototype CB1R ago-PAM, GAT211, yielded new CB1R allosteric modulators (−)-(S,R)-13 and (+)-(R,S)-14, which showed significant bias for CB1R signaling pathways, as supported by docking studies. Compound 14 efficiently lowered elevated intraocular pressure when it is due to an increase in endocannabinoid tone. This article may open new avenues to meet the therapeutic needs presented by glaucoma

Has a “Chemical Magic” Opened up New Prospects for Glaucoma?

Chemical modification of the prototype CB1R ago-PAM, GAT211, yielded new CB1R allosteric modulators (−)-(S,R)-13 and (+)-(R,S)-14, which showed significant bias for CB1R signaling pathways, as supported by docking studies. Compound 14 efficiently lowered elevated intraocular pressure when it is due to an increase in endocannabinoid tone. This article may open new avenues to meet the therapeutic needs presented by glaucoma

Total Synthesis of δ-Sanshool and Analogues Thereof

2nononeTwo simple synthetic approaches were developed for the total synthesis of δ-sanshool, an isobutylamide characterized by a C14 pentaunsaturated chain with all trans double bonds and proposed as a promising lead for the treatment of type-1 diabetes due to its dual activity on cannabinoid (CB) receptors. The syntheses are based on a suitably protected core fragment derived from 1,4-butanediol. These strategies also enable the preparation of small libraries of chemical analogues modified at either the polyunsaturated alkyl chain or the amidic head for use in SAR studies.mixedMugnaini, Claudia; Corelli, FedericoMugnaini, Claudia; Corelli, Federic

Ligandi TRPV1

La presente invenzione concerne composti aventi alta affinità, capaci di legare il recettore canale permeabile ai cationi transient receptor potential, sottofamiglia Vanilloide, tipo 1 o TRPV1. Essendo questo recettore coinvolto in processi dolorosi e in risposte infiammatorie neurogene ed essendo sovra-regolato durante condizioni di dolore cronico, i composti dell’invenzione trovano particolare applicazione in tutte le condizioni mediche coinvolgenti detti recettori, in particolare come agenti per la terapia del dolore e/o antiinfiammatoria e/o della terapia della cefalea a grappolo e/o antiossidante e/o per la terapia antitumorale. Inoltre, la struttura chimica di questi composti fornisce l’opportunità di sviluppare nuovi radiofarmaci per la Positron Emission Tomography (PET) imaging. Questi radiofarmaci sono di notevole importanza per la mappatura dei recettori TRPV1 in condizioni (pato)fisiologiche