In our ongoing program aimed at deeply investigating the endocannabinoid system (ES), a set of new alkyl-resorcinol derivatives was prepared focusing on the nature and the importance of the carboxamide functionality. Binding studies on CB1 and CB2 receptors, monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) showed that some of the newly developed compounds behaved as very potent cannabinoid receptor ligands (Ki in the nanomolar range) while, however, none of them was able to inhibit MAGL and/or FAAH. Derivative 11 was a potent CB1 and CB2 ligand, with Ki values similar to WIN 55,212, exhibiting a CB1 and CB2 agonist profile in vitro. In the formalin test of peripheral acute and inflammatory pain in mice, this compound showed a weak and delayed antinociceptive effect against the second phase of the nocifensive response, exhibiting, interestingly, a quite potent transient receptor potential ankyrin type-1 (TRPA1) channel agonist activity. Moreover, derivative 14, characterized by lower affinity but higher CB2 selectivity than 11, proved to behave as a weak CB2 competitive inverse agonist.

Since the discovery of the endocannabinoid system, evidence has been progressively accumulating to suggest that 2-arachidonoylglycerol (2-AG) rather than anandamide (AEA) is the endogenous ligand for both cannabinoid (CB) receptors. Moreover, other studies have shown that another lipid molecule, 2-arachidonyl-glycerol ether (2-AGE, noladin ether), which acts as a full agonist at cannabinoid receptors, might occur in tissues. Having previously designed a resorcinol AEA hybrid model, in this paper we have explored the cannabinoid receptor binding properties, the CB, functional activity, and the stability to plasma esterases of a novel series of compounds characterized by the conversion of the amide head into the glycerol-ester or glycerol-ether head, typical of 2-AG or the "putative" endocannabinoid 2-AGE, respectively. Glyceryl esters 39 and 41 displayed greater potency for CB, (K, in the nanomolar range) than for CB2 receptors plus the potential to be exploited as useful hits for the development of novel 2-AG mimetics.

The 5-HT(3) receptor (5-HT(3)R) occupies a special place among the serotonin receptor subtypes because it has been shown to be a ligand-gated ion channel, which is involved in a number of physiological functions and important pathologies. 5-HT(3)R antagonists have shown an outstanding efficacy in the control of the emesis induced by anticancer chemotherapy and few adverse side-effects, so as to revolutionize the treatment of nausea in cancer patients. This review covers the authors' work performed during the past decade in the development of 5-HT(3)R ligands belonging to the class of arylpiperazine derivatives related to quipazine (quipazine-like arylpiperazines, QLAs) and represents the extension of the review previously published in Current Topics in Medicinal Chemistry in 2002. The discussion is focused mainly on the most significant structure-affinity relationships emerged in the progress of the work and shows how the original ideas have evolved in the recent years.

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).

This paper reports the results of a study performed to develop a rapid and straightforward chromatographic method for the identification and quantification of trans-resveratrol in commercial trans-resveratrol containing dietary supplements. The method employs an Alltech Platinum EPS 100 A C-18 column operated under isocratic elution mode with a 70:30 (v/v) water-acetonitrile mixture as the mobile phase, at flow rate of 1.0mL min(-1). Peak detection is performed at 306nm with limit of detection (LOD) of 0.27 mu gmL(-1) and limit of quantification (LOQ) of 0.95 mu gmL(-1) and linear calibration graph within the concentration range of 2.63 to 10.53 mu gmL(-1). Other data related to the successful method validation include representative linear regression equation and correlation coefficient of the calibration graph for quantification of trans-resveratrol, as well as the results of replicate analysis of real samples and of a recovery study, carried out to evaluate precision and accuracy, respectively. The method is successfully applied to study the stability of trans-resveratrol in methanol solution under various storage conditions and to analyse commercial preparations of trans-resveratrol containing dietary supplements.

The understanding of the molecular basis of cannabinoid activity has greatly improved since the discovery of CB1 and CB2 receptors. In this paper, the ligand binding processes between the endogenous cannabimimetic ligand, anandamide (AEA), and the cannabinoid receptors from different parts of rat brain were studied by nuclear magnetic resonance spectroscopy. The NMR approach is based on the comparison of selective (R1SE) and non-selective (R1NS) proton spin-lattice relaxation rates of the ligand in the presence and absence of macromolecular receptors, as well as R1NS and R1SE temperature dependency analysis. From these studies, the ligand–receptor binding strength was evaluated on the basis of the calculation of the “affinity index”. The derivation of the “affinity index” from chemical equilibrium kinetics for all systems allowed the comparison of the ability of anandamide to interact with cannabinoid receptors present in different brain sectors.

New oxypropanol alpha- and beta-adrenoceptor blocking agents, analogs of labetalol, were synthesised and studied in vitro in left atria and aorta for alpha and beta activity.

Despite their different chemical structures, Delta(9)-tetrahydrocannabinol (THC) and anandamide (AEA) have common pharmacological properties. This study was aimed at finding new cannabinoid receptor ligands that overcome the instability of AEA and its analogues. To this end we planned the synthesis of a series of compounds which retained both a rigid structure, like that of plant cannabinoids, and a flexible portion similar to that of anandamide. Binding studies on CB1 and CB2 receptors, anandamide membrane transporter (AMT), and fatty acid amide hydrolase (FAAH) showed that some of the newly developed compounds have high affinity and specificity for cannabinoid CB1 and CB2 receptors. Compound 25 is a potent CB1 and CB2 ligand, with affinity constants significantly lower than AEA and similar to WIN 55-212, compound 52 is a potent CB2 ligand, although not very selective over CB1 receptors, and compound 43 is CB2 ligand, with at least a 26-fold selectivity over CB1 receptors. Compound 25 behaved as a inverse agonist at CB1 receptors as assessed in the cyclic AMP functional assay.

The conformational properties of cis-5,8,11,14-eicosatetraenoyiethanolamide (anandamide) were analysed by the combined use of NMR experimental results plus molecular simulations. The structure of anandamide was found to be a predominantly linear with a seven-atom ring of the ethanolamine group having a hydrogen bond which stabilizes the molecule. The vinylic group present has a cis conformation in solution. The terminal chain has a linear conformation and undergoes isotropic fast motion typical of this structure. Copyright (C) 2001 John Wiley & Sons, Ltd.

The synthesis of a new series of sesamol derivatives with β-adrenergic blocking activity is described. The affinity and selectivity of these compounds for β1- and β2-adrenoceptors were studied in comparison with those of ICI-118551 and propranolol. Some of the synthesized compounds show very good affinity for the β2-receptors of rat lung membranes and two of them provide interesting selectivity.

The synthesis of a new series of sesamol derivatives with P-adrenergic blocking activity is described. The affinity and selectivity of these compounds for beta(1)- and beta(2)-adrenoceptors were studied in comparison with those of ICI-118551 and propranolol. Some of the synthesized compounds show very good affinity for the beta(2)-receptors of rat lung membranes and two of them provide interesting selectivity. (C) 1999 Elsevier Science S.A. All rights reserved.

In the search for potential nucleoside/non-nucleoside mixed type inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase, we synthesized a new set of rifamycin S derivatives, containing AZT connected via its hydroxyl at 5′ C, through a spacer, to the third C of rifamycin S. The length of the spacer was eight, nine or 14 atoms. Rifamycin S was also used in its 21, 23-O, O-isopropylidene derivative form, and in one case thymidine replaced AZT. These nucleosidyl rifamycins were weak inhibitors of isolated HIV-1 reverse transcriptase. The inhibitory power was weak most probably because their large molecular volume hindered the inhibition process. With the exception of the thymidine derivative, the AZT derivatives, at concentrations in the range 0.04–0.07 μM, proved non-toxic and inhibited the replication of HIV-1 in C8166 T lymphocytes. This activity appears to be owing to AZT released by the derivatives upon hydrolysis in solution. The present compounds require further development as mixed type reverse transcriptase inhibitors and can be considered non-toxic lipophilic prodrugs of AZT.

Three types of open ansa-chain rifamycin S derivatives have been prepared: derivatives with the ansa-chain open at C(29) and the original dihydrofuranone ring; derivatives with the ansa-chain open at C(29) and a furane ring; derivatives with the ansa-chain at open NH-C(15). Only derivatives of the first type are weak inhibitors of HIV-1 reverse transcriptase (IC50 ca.300 microM) while derivatives of the two other types are inactive. It has been hypothesized that the active derivatives inhibit the viral enzyme interacting through the groups C(14)H3, C(13)H3, and C(1)O at the same site as the well-known inhibitors TIBO and Nevirapine. In particular C(13)H3 must be unhindered and in an appropriate position out of the plane containing the chromophore-rings. The open ansa-chain seems to play the role of a lipophylic substituent.

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29 Rifamycins were tested for inhibition of Reverse Transcriptase (RT) as potential anti HIV drugs. Two purified commercial enzymes from M-MuLV and RAV-2 were used. Anti-RT activity was also measured on a crude lysate of HIV-1. The results show that some derivatives have interesting levels of activity on isolated M-MuL V and RA V-2 RTs, while they are less active on the RT in the crude HIV-1 lysate. The active derivatives include oximes and hydrazones, alkylaminoderivatives, open ansa-chain derivatives and derivatives carrying a modified nucleoside.

The inhibitory activity of a series of 2- and 4-quinolinehydrazones on retroviral reverse transcriptase has been studied on enzymes from M-MuLV, RAV-2, and on a crude lysate of HIV-1, assuming the first two enzymes as potential models of the third. The highest activity is mainly found in lipophilic, water soluble 4-quinolinehydrazones. The inhibitory activity of these compounds decreases in changing from the M-MuLV to the RAV-2, and HIV-1 enzymes, in this order.

In order to obtain derivatives with simultaneous alpha- and beta-adrenergic blocking activity, compounds having the phenoxypropanolaminic structure of beta-adrenergic blockers have been synthesised, as well as 1,2,4-oxadiazole moiety, which could imitate the imidazolinic nucleus characteristic of drugs acting on alpha-adrenergic receptors. The synthesised compounds have been submitted to alpha and beta receptor binding assays. Some derivatives showed an alpha-adrenoceptor binding activity higher than labetalol and similar to prazosin, but with a poor beta-adrenoceptor binding activity.