No abstract

A series of 18 1-[(1,2-diphenyl-1H-4-imidazolyl)methyl]-4-piperazines (1a-r) were designed and synthesized as possible ligands with mixed dopamine (DA) D(2)/serotonin 5-HT(1A) affinity, with the aim of identifying novel compounds with neurochemical and pharmacological properties similar to those of clozapine. The binding profile at D(2) like, 5-HT(1A), and 5-HT(2A) receptors of title compounds was determined. Modifications made in the phenyl rings of the parent compound (1a) produced congeners endowed with a broad range of binding affinities for DA D(2) like, serotonin 5-HT(1A), and 5-HT(2A) receptors, with IC(50) values ranging from 25 to >10,000 nM. As for the modification of the piperazine N(4)-phenyl ring, the affinities for both D(2) like and 5-HT(1A) receptors were progressively increased by introduction of ortho-methoxy and ethoxy groups (1b,o, respectively). Data revealed the presence of a para-chloro substituent in 1g to be associated with a relatively high affinity and substantial selectivity for D(2) like receptors, whereas the meta-chloro analogue 1f exhibited preferential affinity for 5-HT(1A) receptors. A quantitative structure-affinity relationship analysis of the measured binding data resulted in regression equations that highlighted substituent physicochemical properties modulating the binding to subtypes 1A and 2A of serotonin 5-HT receptors but not to D(2) like receptors. Thus, besides an electron-withdrawing field effect and ortho substitution, which both influence binding to serotonin 5-HT receptor subtypes, though to a different extent as revealed by regression coefficients in the multiparametric regression equations, the affinity of congeners 1a-r to 5-HT(1A) receptors proved to be linearly correlated with volume/polarizability descriptors, whereas their affinity to 5-HT(2A) receptors correlated with lipophilicity constants through a parabolic relationship. 1-[(1,2-Diphenyl-1H-4-imidazolyl)methyl]-4-(2-methoxyphenyl)piperazine (1b), with a D(2)/5-HT(1A) IC(50) ratio of approximately 1, was selected for a further pharmacological study. In rats, the intraperitoneal administration of compound 1b, like that of clozapine, induced an increase in the extracellular concentration of DA measured in the medial prefrontal cortex. Furthermore, 1b and clozapine each inhibited GABA-evoked Cl(-) currents at recombinant GABA(A) receptors expressed in Xenopus oocytes. These findings suggest that compound 1b may represent an interesting prototype of a novel class of drugs endowed with a neurochemical profile similar to that of atypical antipsychotics.

A series of novel 1,3,4-oxadiazoles was synthesized and evaluated for their cytotoxic activity in in vitro tumor models. Four of the new compounds (2d, 2j, 2k, and 2n) showed growth inhibition in the XTT dye assay. The most active agent, 2j, showed high potency against human cancer cells with ICs ranging from 0.05 to 1.7 μM. Preliminary SAR correlations suggested that the nature of chains on the oxadiazole is important for antitumor potency in vitro. Compound 2j determined a G/M arrest of the cell cycle and also activated a strong apoptotic response. The β-tubulin immunofluorescence analysis indicated that compound 2j effectively inhibited the microtubule organization in all cancer cell lines, causing the formation of abnormal spindle, which did not affect the normal human fibroblast cells NB1, Mrc-5 and IBR3. For all these reasons, compound 2j could be a good candidate in chemopreventive or chemotherapeutic strategies.

Designed as a new group of tricyclic molecules containing the thienocycloheptapyridazinone ring system, a number of 2N-substituted-hexahydrothieno-cycloheptapyridazinone derivatives were synthesized and their biological activity evaluated. Among the synthesized compounds, derivatives 7d and 7h were found to possess cytotoxic activity against non-small cell lung cancer and central nervous system cancer cell lines, respectively.

No abstract

A series of new 1,2-diphenylimidazole derivatives (1a-x) were synthesized and evaluated for their ability to potentiate gamma-aminobutyric acid (GABA)-evoked currents in Xenopus laevis oocytes expressing recombinant human GABA(A) receptors. Many of these compounds enhanced GABA action with potencies (EC(50) = 0.19-19 muM) and efficacies (maximal efficacies of up to 640%) similar to or greater than those of anesthetics such as etomidate, propofol, and alphaxalone. Structure-activity relationship analysis revealed that the presence of an ester moiety in the imidazole ring was required for full agonist properties, while modifications made in the phenyl rings affected potency and efficacy, with ethyl 2-(4-bromophenyl)-1-(2,4-dichlorophenyl)-1H-4-imidazolecarboxylate showing the highest potency. These compounds potentiated the [(3)H]GABA binding to rat brain membranes, suggesting a site of interaction different from that of GABA. As for etomidate, mutation of asparagine-265 in the beta2 subunit of the GABA(A) receptor into serine reduced the ability of derivative 1i to modulate the GABA function.

No abstract

The search of new drugs and targets to treat the pain is an intriguing challenge both for several companies and researchers from academia. In this context, since the modulation of the endocannabinoid system with the non selective phytocannabinoid Δ9-THC produces analgesia and potentiates opioid analgesia in animal models, CB2 ligands studies aimed to explore the involvement of endocannabinoid system in management of pain were started. Several selective CB2 receptor agonists exhibited analgesic activity in preclinical models of acute, inflammatory and neuropathic pain, therefore this class of modulators could be useful as analgesic agents for pain, migraine, inflammation and osteoarthritis. This review is an update of our previously manuscript "A survey of recent patents on CB2 agonists in the management of pain" and provides an overview of patents and advances in CB2 agonist studies in the treatment of pain.