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Summary A set of 1-methyl-2-(4-X-benzoyl)imidazole-5-carboxylic acids, designed as antiinflammatory—analgesic agents, were synthesized and biologically evaluated in vivo (writhing test and the carrageenen rat pleurisy) using tolmetin as a reference drug. The compounds were also tested in vitro on the cyclooxygenase enzyme of sheep vescicular microsome. Distribution coefficients in the octanol-buffer system at different pH values have been determined for their potential influence on activity. Although the investigated compounds exhibited moderate or no inhibitory activity against cyclooxygenase in in vitro and in vivo assays, two of them (the 4-nitrobenzoyl and the 4-chlorobenzoyl derivatives 1e and 1b ) were found to be more active than tolmetin in the writhing test. Moreover, 1b also showed higher activity in the pleurisy assay.

Glaucoma is a group of eye diseases consisting of optic nerve damage with corresponding loss of field vision and blindness. Hydrogen sulfide (H2S) is a gaseous neurotransmitter implicated in various pathophysiological processes. It is involved in the pathological mechanism of glaucomatous neuropathy and exerts promising effects in the treatment of this disease. In this work, we designed and synthetized new molecular hybrids between antiglaucoma drugs and H2S donors to combine the pharmacological effect of both moieties, providing a heightened therapy. Brinzolamide, betaxolol and brimonidine were linked to different H2S donors. The H2S-releasing properties of the new compounds were evaluated in a phosphate buffer solution by the amperometric approach, and evaluated in human primary corneal epithelial cells (HCEs) by spectrofluorometric measurements. Experimental data showed that compounds 1c, 1d and 3d were the hybrids with the best properties, characterized by a significant and long-lasting production of the gasotransmitter both in the aqueous solution (in the presence of L-cysteine) and in the intracellular environment. Because, to date, the donation of H2S by antiglaucoma H2S donor hybrids using non-immortalized corneal cells has never been reported, these results pave the way to further investigation of the potential efficacy of the newly synthesized compounds.

The HIV-1 nucleocapsid (NC) protein represents an excellent molecular target for the development of anti-retrovirals by virtue of its well-characterized chaperone activities, which play pivotal roles in essential steps of the viral life cycle. Our ongoing search for candidates able to impair NC binding/annealing activities led to the identification of peptidyl-anthraquinones as a promising class of nucleic acid ligands. Seeking to elucidate the inhibition determinants and increase the potency of this class of compounds, we have now explored the effects of chirality in the linker connecting the planar nucleus to the basic side chains. We show here that the non-natural linker configuration imparted unexpected TAR RNA targeting properties to the 2,6-peptidyl-anthraquinones and significantly enhanced their potency. Even if the new compounds were able to interact directly with the NC protein, they manifested a consistently higher affinity for the TAR RNA substrate and their TAR-binding properties mirrored their ability to interfere with NC-TAR interactions. Based on these findings, we propose that the viral Tat protein, sharing the same RNA substrate but acting in distinct phases of the viral life cycle, constitutes an additional druggable target for this class of peptidyl-anthraquinones. The inhibition of Tat-TAR interaction for the test compounds correlated again with their TAR-binding properties, while simultaneously failing to demonstrate any direct Tat-binding capabilities. These considerations highlighted the importance of TAR RNA in the elucidation of their inhibition mechanism, rather than direct protein inhibition. We have therefore identified anti-TAR compounds with dual in vitro inhibitory activity on different viral proteins, demonstrating that it is possible to develop multitarget compounds capable of interfering with processes mediated by the interactions of this essential RNA domain of HIV-1 genome with NC and Tat proteins.

Isonicotinamide derivatives, linked to an arylpiperazine moiety, were prepared and their affinity to 5-HT 1A , 5-HT 2A and 5-HT 2C receptors were evaluated. The combination of structural elements (heterocyclic nucleus, alkyl chain and 4-substituted piperazine) known to play critical roles in affinity for serotoninergic receptors and the proper selection of substituents led to compounds with high specificity and affinity towards serotoninergic receptors. In binding studies, several molecules showed high affinity in nanomolar and subnanomolar range at 5-HT 1A , 5-HT 2A and 5-HT 2C receptors and moderate or no affinity for other relevant receptors (D 1 , D 2 , α 1 and α 2 ). N -(3-(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)propyl)isonicotinamide ( 4s ) with Ki = 0.130 nM, was the most active and selective derivative for the 5-HT 1A receptor compared to other serotoninergic, dopaminergic and adrenergic receptors. Compound 4o , instead, showed 5-HT 2A affinity values in subnamolar range. Moreover, the compounds having better affinity and selectivity binding profile towards 5-HT 1A and 5-HT 2A receptors were selected in order to be tested by in vitro and in vivo assays to determine their functional activity.

Hydrogen sulfide (H2S) is an endogenous modulator that plays significant physio-pathological roles in several biological systems. In this research field there is a large interest in developing selective CBS and CSE inhibitors and H2S releasing moieties, that could be either used as therapeutic agents or linked to known drugs. One of the major problem is the limited availability of chemicals that ensure a controlled release of H2S in vitro as well in vivo. Aiming to obtain novel H2S donors, whose release properties could be appropriately modulated, we have synthesized a series of 1,2,4-thiadiazolidine-3,5-diones (THIA 1–10) as innovative donors that could release H2S in controlled manner. All the synthesized compounds were evaluated for their H2S releasing properties by an amperometric approach and for their vasorelaxant ability on aorta rings. In order to rationalize the obtained results, a detailed study on the release mechanism has been performed using the most efficient H2S donor, THIA 3 (Cmax 65.4 μM and EC50 1.7 μM).

The 5-HT1A receptor is a pharmacologically well characterized serotonin receptor subtype and it has long been investigated because of its involvement in several physiopathological mechanisms and treatment of neurological diseases like ansia and depression. Serotonin (5-HT) also shows many non-neural functions such as essential hypertension, embryogenesis, follicle maturation and behavior. Moreover, it exerts a growth factor function on different types of non-tumoral cells, and it was also found to be related to oncogenes. In fact, growth-stimulatory activity of serotonin in different human tumor cells has been reported. Recently, new chemical molecules binding the 5-HT1A receptor have been described as novel therapeutic entities useful in neuroprotection, cognitive impairment, Parkinson’s Disease, pain treatment, malignant carcinoid syndrome and cancer. It was widely demonstrated that 5-HT1A receptor is involved in the carcinogenesis and consequently in many human tumor types, such as prostate, bladder, small cell lung, colonrectal and cholangiocarcinoma. Furthermore, depending on the tumor type, 5-HT1A receptor antagonists were shown to be capable of blocking the 5HT-induced increase in tumor growth. In this review, we have focused our attention on each tumor type where the 5-HT1A receptor is involved, investigating the role of this molecular target and the different classes of compounds that have shown the capability to modulate it. The analyzed aspects could represent a hint for the medical chemists to develop novel molecules as selective 5-HT1A agents are useful in further elucidating the role of this therapeutic target.

Two series of N-(aryl)-1-(hydroxyalkyl)pyrrolidine-2-carboxamides (2a-2g and 3a-3g) and 1,4-disubstituted 1,2,3-triazoles (5a-5h and 8a-8h) were synthesized. All the compounds, containing a lipophilic tail and a polar headgroup, were evaluated as sphingosine kinase (SphK) inhibitors by assessing their ability to interfere with the acetylcholine (Ach) induced relaxation of aortic rings pre-contracted with phenylephrine. Moreover, their antiproliferative activity was tested on several cell lines expressing both SphK1 and SphK2. Compounds 5h and 8f, identified as the most efficient antiproliferative agents, showed a different selectivity profile, with 8f being selective for SphK1.

Picolinamide derivatives, linked to an arylpiperazine moiety, were prepared and their affinity to 5-HT1A, 5-HT2A and 5-HT2C receptors was evaluated. The combination of structural elements (heterocyclic nucleus, alkyl chain and 4-substituted piperazine), known to play critical roles in affinity for serotoninergic receptors, and the proper selection of substituents led to compounds with high specificity and affinity towards serotoninergic receptors. In binding studies, several molecules showed high affinity in nanomolar and subnanomolar range at 5-HT1A, 5-HT2A and 5-HT2C receptors and moderate or no affinity for other relevant receptors (D1, D2, 1 and 2). N-(2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)picolinamide (3o) with Ki = 0.046 nM, was the most affine and selective derivative for the 5-HT1A receptor compared to other serotoninergic dopaminergic and adrenergic receptors. N-(2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl)picolinamide (3b), instead, showed a subnanomolar affinity towards 5-HT2A with Ki = 0.0224 nM, whereas N-(2-(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)ethyl)picolinamide (3s) presented an attractive 5-HT2C affinity with Ki = 0.8 nM. Moreover, the compounds having better affinity and selectivity binding profiles towards 5-HT2A were selected and tested on rat ileum, to determine their effect on 5HT induced contractions. Those more selective towards 5-HT1A receptors were studied in vivo on several behavioral tests.

A new set of 5-(2-(pyrrolidin-1-yl)acetamido)- N -butyl-2-(substituted)benzamide and 5-(2-(piperidin-1-yl)acetamido)- N -butyl-2-(substituted) benzamide derivatives were synthesized in which as structural features the 2-(1-pyrrolidinyl)- or 2-(1-piperidyl)acetylamino group or a diphenylether moiety are associated to a benzamide scaffold. Their binding affinity for human PrP C and inhibition of its conversion into PrP Sc were determined in vitro; moreover, the antiprion activity was assayed by inhibition of PrP Sc accumulation in scrapie-infected mouse neuroblastoma cells (ScN2a) and scrapie mouse brain (SMB) cells. The results clearly indicate the benzamide derivatives as attractive lead compounds for the development of potential therapeutic agents against prion disease.

N'-cyanoisonicotinamidine derivatives, linked to an arylpiperazine moiety, were prepared to identify highly selective and potent 5-HT(1A) ligands as potential pharmacological tools in studies of wide spread psychiatric disorders. The combination of structural elements (heterocyclic nucleus, alkyl chain and 4-substituted piperazine) known to be critical in order to have affinity on 5-HT(1A) receptor and the proper selection of substituents led to compounds with high specificity and affinity towards serotoninergic receptors. In binding studies, several molecules showed affinity in nanomolar and subnanomolar range at 5-HT(1A) and moderate to no affinity for other relevant receptors (5-HT(2A), 5-HT(2C), D(1), D(2), alpha(1) and alpha(2)). N'-cyano-N-(3-(4-(pyridin-2-yl)piperazin-1-yl)propyl)isonicotinamidine (4o) with K(i)=0.038 nM, was the most active and selective derivative for the 5-HT(1A) receptor with respect to other serotoninergic, dopaminergic and adrenergic receptors.

Protease-activated receptor-1 (PAR-1) is a G-coupled receptor activated by α-thrombin and other proteases. In this paper we describe the synthesis and the pharmacological evaluation of novel peptide-mimetic antagonists (compounds 1 – 16 ) characterized by the presence of new heterocyclic nuclei such as 2-methyl-indole (5- and 6-substituted) and 1,4-benzodiazepine moiety. The new derivatives, tested in order to evaluate their antagonist potency by using human platelet aggregation induced by PAR-1AP, resulted in some cases (compounds 1 and 4 ) more potent than the reference. The compounds, tested on aortic rings, confirmed the results obtained in the aggregation assay.

1,3 Dipolar cycloaddition of Fmoc-amino azides and acetylenic amides produces under solvent free irradiation a mixture of 1,4 or 1,5 substituted [1,2,3]-triazoles. The presence of copper (I) iodide, plays a central role on regioselectivity. Four Fmoc-amino azides characterized by different steric hindrance in side chains, and three different terminal alkynes, provided only the 1,4 substituted regioisomer under thermal microwave heating. Good yields, low consumption of organic solvents and short reaction times are the main aspects of our procedure. Reactions are compared to regioselective copper (I) catalysed solution synthesis performed at room temperature.

Heterocyclic compounds hold a special place among pharmaceutically important natural and synthetic materials. The remarkable ability of heterocyclic nuclei to serve both as biomimetics and reactive pharmacophores has largely contributed to their unique value as traditional key elements of numerous drugs. In both lead identification and optimization processes there is an acute need for new organic small molecules. Traditional methods of organic synthesis are orders of magnitude too slow to satisfy the demand for these compounds; so, the fields of combinatorial and automated medicinal chemistry have been developed to meet the increasing requirement of new compounds for drug discovery, within these fields, speed is of the essence. The efficiency of microwave flash-heating chemistry in dramatically reducing reaction times (reduced from days and hours to minutes and seconds) has recently been proven in several different fields of organic chemistry. We believe that the time saved by using focused microwaves is potentially important in traditional organic synthesis but could be of even greater importance in high-speed combinatorial and medicinal chemistry. In this review, it is impossible to cover all significant developments in the area of microwave-assisted organic synthesis (MAOS). Rather, outlines the basic principles behind the technology and summarizes the areas in which microwave technology has made an impact, to date. Specific attention is given to application of microwave technology in Combinatorial Organic Synthesis of several representative biologically interesting nuclei obtained both in liquid systems and in the solid state.

An efficient, facile, and practical parallel combinatorial synthesis of substituted-benzoxazines under microwave irradiation was described. The procedure involved the use of a microwave oven especially designed for organic synthesis suitable for parallel synthesis of solution libraries. A demonstration 19-membered library of substituted N,N-dimethyl- and N-methyl-benzoxazine amide derivatives, structurally related to the potassium channel opener cromakalim, was generated by both conventional and microwave procedures, achieving a reduction from 7 h to 30-36 min in library generation time for the microwave approach. All the synthesized compounds were tested using the in vitro models of rat aorta and guinea pig trachea rings pre-contracted with phenylephrine and carbachol, respectively. All N,N-dimethyl amide derivatives showed a relaxant activity higher on guinea pig trachea rings than on rat aorta rings.

A novel and convenient microwave-assisted synthesis of an active metabolite (EXP-3174) of losartan is described. Room temperature and microwave irradiation of the reactions are compared. Synthesis by microwave irradiation gave the desired compound in higher yields and in shorter reaction times than those obtained at room temperature. © 2003 Elsevier Science Ltd. All rights reserved.

A novel and convenient microwave-assisted dimerization of an active peptide compound using the DKPs as scaffold is described. The key reaction giving rise to the diketopiperazine scaffold is the intermolecular coupling. No epimerization was detected in the reactions used. Conventional and microwave heating of the reactions are compared. Synthesis by microwave irradiation gave the desired compounds in higher yields and in shorter reaction times than those obtained by conventional heating. © 2003 Elsevier Science Ltd. All rights reserved.

2-Methyl-1,4-benzodiazepin-5-ones were synthesized from isatoic anhydrides via cyclization of N-allyl-2-aminobenzamides with application of microwave irradn. Conventional heating and microwave irradn. of the reactions were compared. Synthesis by microwave irradn. gave the desired compds. in better yields than by conventional heating. Overall times for the syntheses were considerably reduced.

Peptide T (ASTTTNYT), a fragment corresponding to residues 185-192 of gp120, the coat protein of HIV, is endowed with several biological properties in vitro, notably inhibition of the binding of both isolated gp120 and HIV-1 to the CD4 receptor, and chemotactic activity. Based on previous nuclear magnetic resonance (NMR) studies performed in our laboratory, which were consistent with a regular conformation of the C-terminal pentapeptide, and SAR studies showing that the C-terminal pentapeptide retains most of the biological properties, we designed eight hexapeptides containing in the central part either the TNYT or the TTNY sequence, and charged residues (D/E/R) at the two ends. Conformational analysis based on NMR and torsion angle dynamics showed that all peptides assume folded conformations, albeit with different geometries and stabilities. In particular, peptides carrying an acidic residue at the N-terminus and a basic residue at the C-terminus are characterized by stable helical structures and retain full chemotactic activity. The solution conformation of peptide ETNYTR displays strong structural similarity to the region 19-26 of both bovine pancreatic and bovine seminal ribonuclease, which are endowed with anti-HIV activity. Moreover, the frequent occurrence, in many viral proteins, of TNYT and TTNY, the two core sequences employed in the design of the hexapeptides studied in the present work, hints that the sequence of the C-terminal pentapeptide TTNYT is probably representative of a widespread viral recognition motif. Copyright © 2001 European Peptide Society and John Wiley & Sons, Ltd.

Anumber of 1- and 2-(4-arylpiperazinylalkyl)-4-(benzoyl)-1,2,3-triazole derivatives (1–4) were prepared in order to obtain compounds with a high affinity and selectivity for 5-HT 1A receptors. 5-HT 1A, 5-HT 2A and 5-HT 2C affinities were determined by radioligand binding experiments and the most active compounds were also tested for binding affinities on dopaminergic D-1, D-2 and adrenergic α 1 , α 2 receptors. The modification of aromatic substituents, the length of the alkyl chain and its position on the 4-benzoyl-1,2,3-triazole ring were explored. Most of the considered compounds generally showed moderate to high affinity for the 5-HT 1A receptor binding site. Three derivatives 2c , 3c and 3e bind to 5-HT 1A receptors in the nanomolar range (IC 50 values = 2, 7.2 and 2.6 nM respectively). The most active compound, 2c , presented a high degree of selectivity versus all considered receptors. It was found that the benzoyltriazole derivatives 1h and 4c are new selective ligands for 5-HT 2A (IC 50 = 89 nM) and 5-HT 2C receptors (IC 50 = 17 nM), respectively.

We designed, synthesized and tested novel 2,6-disubstituted-anthraquinones able to bind dynamic secondary structures of nucleic acids, such as TAR RNA and its reverse transcript cTAR, leading to inhibition of the chaperone activities of the nucleocapsid NCp7, a highly conserved viral protein implied in crucial steps of HIV-1 replication.

To obtain information about the structure-activity relationships of analgesic peptides, we modified the previously reported tripeptide, H-Lys-Pro-Thr-OH (C). The proline part in C was replaced with various analogues of unconventional amino acids {(3aS, 7aS)-octahydroindole-2-carboxylic acid (Oic), (S,S,S,)-2-azabiciclo [3.3.0] octane-3-carboxylic acid (Aoc), D-Aoc, and (2S, 4R)-hydroxyproline (Hyp)} with varying lipophilic, steric, and conformational properties, and alternatively with Lys and Orn in the lysine part. Moreover, the threonine part was changed to various natural amino acids (Ser, Thr, Val, Leu). All the compounds were screened in vivo for their analgesic effects in mouse writhing test. Compound 24 (H-Orn-Hyp-Val-OH), the most active compound within the series, showed an ED50 value of 10 mg/kg, which is comparable with the ED50 values exhibited by indometacin (4.1 mg/kg) and the dipeptide H-Lys-D-Pro-OH (6.9 mg/kg), both used as reference drugs. © 1997 John Wiley & Son's, Inc. Biopoly 40: 479–484, 1996

Summary A number of benzotriazole derivatives have been assayed in radioligand binding experiments involving the following recombinant human serotonin receptors: 5-HT 2A , 5-HT 1A , 5-HT 1Dβ and 5-HT 2C . Several of the compounds tested show interesting selectivity profiles. In particular, the affinities of 3d, 4a and 4d for teh 5-HT 2A subtype (with p K i values of 7.4, 7.4 and 8.0, respectively) are between 100 and 1000 times higher than for the other investigated receptors. Compound 51 , characterized by a p K i value of 7.4 on the 5-HT 1A receptor, binds with 100- to 1000-fold lower potencies on the other receptors. Our benzotriazole derivatives are generally weak ligands of the 5-HT 1Dβ and 5-HT 2C receptors. Structure—affinity relationship data suggest that not all the compounds exhibit the same binding mode at the 5-HT 2A and 5-HT 1A receptors.

Summary A set of N -[2-(alkylamino)ethyl]benzotriazol- X -yl isobutyramides have been synthesized and assayed in vivo for their local anesthetic activity and acute toxicity. Some of them showed a more favorable pharmacological profile than that of the reference drug lidocaine. QSAR studies have delineated the influence of overall lipophilicity on surface and infiltration anesthetic activities.

One pot microwave-assisted synthesis of substituted 1,2,4-oxadiazoles I (R = H. NO2, OEt), in solvent and under solvent free condition, was performed exploring the importance of some coupling reagents. Good yields and short reactions time were the main aspects of the methods.

A series of 1- and 2-[3-[4-( X )-1-piperazinyl]-propyl]benzotriazoles were prepared and evaluated for their trazodone-like pharmacological profile; as preliminary pharmacological screening, the compounds were tested for their antiserotonergic, antiadrenergic and antihistaminic in vitro activity as well as for their analgesic in vivo action. Structure-activity relationships showed that among the synthesized compounds, the analogues bearing on the 4-piperazine nitrogen either an unsubstituted phenyl ring or a 2- or 3-chloro phenyl moiety show a pharmacological profile similar to that of the antidepressant trazodone.

The difficult coupling of a-aminoisobutyric acid (Aib), during the synthesis of dipeptides [Z-Aib-Val-OMe, Z-Val-Aib-OMe, Z-Aib-Ile-OMe, Boc-Ile-Aib-OMe, Z-Aib-Aib-OMe, Boc-Aib-Aib-OMe, (Z = benzyloxycarbonyl, Boc = tert-butoxycarbonyl)], was carried out using PyBOP/HOBt and HBTU/HOBt reagents by application of microwave energy in the presence of solvent. Room temp., conventional heating (oil bath) and microwave irradn. of the reactions are compared. Synthesis by microwave irradn. gave the desired compds. in higher yields and in shorter reaction times than those obtained by conventional heating or at room temp.

Serotonin (5-hydroxytryptamine, 5-HT) is one of the most important neuromediator involved in numerous physiological and pathophysiological processes. In addition it is well established that 5-HT acts as a growth factor on several types of non-tumoral and tumoral cells, and recently it was also related to oncogenes. 5-HT1A receptor expression was identified in prostatic tumor cell lines (PC3 cells) and in human hormone refractory prostate cancer tissue. Based on these observations, development of 5-HT1A antagonists could be useful in inhibiting the growth of cancer cells. In order to investigate on potential use of 5-HT1A ligands as antiproliferative agents, we have analyzed a new set of 1-naphtylpiperazine derivatives. In binding studies, several molecules showed affinity in nanomolar and subnanomolar range at 5-HT1A and moderate to no affinity for other relevant receptors (5-HT2A, 5-HT2C, D1, D2, α1 and α2). All compounds were then evaluated in order to assess their antiproliferative activity using PC3 cells and the most active compounds (1 and 2) were fully characterized to define the mechanism responsible for the observed antiproliferative effect.

Gaseous transmitters are a growing family of regulatory molecules involved in multilevel regulation of physiological and pathological functions in mammalian tissues. Hydrogen sulfide (H2S) is best known for its characteristic smell of rotten eggs. It is now widely recognized that H2S, along with nitric oxide (NO) and carbonmonoxide (CO), is involved in a multitude of physiological functions. The generation of H2S bymammalian tissues is likely to occur in a slow and constant rate, and it appears to be involved in several processes including neuromodulation, hypertension, inflammation, edema, hemorrhagic shock, pain perception, gastric mucosal integrity, and vascular tone. This Perspective has been designed in order to give to the reader an updated overview on the physiology and biochemistry of H2S. In particular we have summarized the effects of H2S inhibitors and H2S donors in animal models of disease ordered for apparatus. Finally there is a section that addresses the potential for therapeutic exploitation ofH2S and provides an update on the patents so far filed.

An easy and convenient microwave-assisted synthesis of a small library of indolic arylpiperazine derivatives is described. Parallel and mixed pool combinatorial methods are reported and compared. The described reactions are nucleophilic substitutions of several aromatic piperazines in presence of K(2)CO(3). Good yields and short reaction times are the main aspect of these procedures. Binding assays shed additional light on the influence of the LCAPs on the 5-HT(1A), 5-HT(2A) and 5-HT(2C) receptors affinity and allowed to disclose three interesting compounds as 5-HT(2C), mixed 5-HT(2A)/5-HT(2C) and 5-HT(1A)/5-HT(2C) ligands (4i, 4l and 4d, respectively), with potential antiepileptic, anxiolytic or atypical antipsychotic agent therapeutical profiles.

In this paper, we describe the synthesis of conformationally constrained dipeptide mimetic derivatives. Microwave flash heating was used in several synthetic steps providing the opportunity to perform the reactions in dramatically shortened time as well as to increase the obtained yields. The efficiency of the methodology makes it useful in order to prepare other dipeptides containing the 4-amino-tetrahydro-2- benzazepin-3-one motif.

Increase of VPAC receptor s binding to the (16)gamma-glutamyl diaminopropane vasoactive intestinal peptide (VIP-DAP) agonist, a vasoactive intestinal polypeptide (VIP) structural analogue containing a positive charge at position 16, has confirmed the importance of a positive charge at this site. By investigating the effect of distance from the peptide backbone Calpha of a positive charge in position 16, data are reported here concerning: (i) a novel chemical method used for the synthesis of a new family of (16)gamma-glutamyl diamine VIP derivatives differing among them for single carbon atoms and including diaminoethane (VIP-DAE2), diaminopropane (VIP-DAP3), diaminobutane (VIP-DAB4), diaminopentane (VIP-DAP5), and diaminohexane (VIP-DAH6); (ii) functional characterization of these compounds on human VPAC1 and VPAC2 receptors. In more detail, the EC50 and IC50 values, when measured as a function of the alkylic chain length, show in more detail, that the use of VIP-DAB4 derivative changes the IC50 but not the EC50, thus indicating on hVPAC2 receptor an unexpected relationship between binding and activity that differs from that obtained on hVPAC1.

We report microwave-assisted synthetic routes, the pharmacokinetic profile along with results from ulcerogenicity and mutagenicity studies of atenolol aspirinate, and an already described derivative, in which acetyl salicylic acid (aspirin®) was connected to atenolol by an ester linkage. Atenolol aspirinate was stable towards aqueous hydrolysis but rapidly hydrolyzed in plasma (t 1/2 = 7.6 min). The results showed that the rapid and complete hydrolysis generates atenolol salicylate, which assumes a conformation stabilized by two intramolecular H-bonds, avoiding its further hydrolysis to salicylic acid and atenolol.

Three series of compounds characterized by biphenylic structure were synthesized in order to develop new scaffolds able to induce β-sheet folding in the peptides. Microwave flash heating was used in order to shorten reaction times and to enhance the obtained yields. Simulated annealing molecular dynamics simulations demonstrated that some of the compounds were capable of adopting a 15-membered intramolecularly hydrogen-bonded conformation, which supports an antiparallel β-sheet structure.

Peptide T (ASTTTNYT), a segment corresponding to residues 185–192 of gp120, the coat protein of HIV, has several important biological properties in vitro that have stimulated the search for simpler and possibly more active analogs. We have previously shown that pseudocyclic hexapeptide analogs containing the central residues of peptide T retain considerable chemotactic activity. We have now extended the design of this type of analogs to peptides containing different aromatic residues and/or Ser in lieu of Thr. The complex conformation-activity relationship of these analogs called for a reexamination of the basic conformational tendencies of peptide T itself. Here, we present an exhaustive NMR conformational study of peptide T in different media. Peptide T assumes a γ-turn in aqueous mixtures of ethylene glycol, a type-IV β-turn conformation in aqueous mixtures of DMF, and a type-II β-turn conformation in aqueous mixtures of DMSO. The preferred conformations for the analogs were derived from modeling, starting from the preferred conformations of peptide T. The best models derived from the γ-turn conformation of peptide T are those of peptides XII (DSNYSR), XIII (ETNYTK) and XVI (ESNYSR). The best models derived from the type-IV β-turn conformation of peptide T are those of peptides XIV (KTTNYE) and XV (DSSNYR). No low-energy models could be derived starting from the type-II β-turn conformation of peptide T. The analogs with the most favored conformations are also the most active in the chemotactic test. Copyright © 2007 European Peptide Society and John Wiley & Sons, Ltd.

In this study, the mutagenicity of the anti-inflammatory parsalmide [5-amino-N-butyl-2-(2-propynyloxy)-benzamide] analogues PA7 [5-amino-N-butyl-2-cyclohexyloxy-benzamide], PA10 [5-amino-N-butyl-2-phenoxy-benzamide] and PA31 [5-amino-N-butyl-2-(p-tolyloxy)-benzamide] was determined by an Ames Salmonella assay. The experiments were performed by preincubating the compounds in the absence and presence of a post-mitochondrial fraction (S9) of rat liver homogenate from phenobarbital/beta-naphtoflavone treated rats. No mutagenic effect was observed after direct testing (no S9 added) in Salmonella typhymurium strains TA98, TA100, TA102, TA1535 and TA1537. However, in the presence of S9, the test substances triggered mutagenic responses in strains TA100 and TA98. PA31 presented the strongest mutagenic potential. The reversion rates in the presence of PA31 were about 2-19 fold higher than spontaneous mutation rates. In the presence of PA7, the reversion increased 2-14-fold over spontaneous rates. While PA10 showed a relatively mild mutagenic potential, as the number of revertants did not exceed 2.5 times the number of spontaneous mutations. Mass spectrometric analysis of the in vitro biotransformation showed that S9 converted (%), regioselectively, PA7 (19%), PA10 (7%) and PA31 (12%) into hydroxy-derivatives.

The synthesis by microwave irradiation and the biological results of novel benzotriazinone and saccharine derivatives with potential antidiarrhoeal activity is described. Conventional and microwave heatings were compared for the reactions. Good yields and short reaction times are the main advantages of our synthetic route. Among the tested compounds, compound 12 inhibited motility both in in-vitro and in-vivo tests.

Serotonin is a neuromediator, well-know for its implication in mood regulation, anxiety, depression and, insomnia as well as in normal human function such as sleep, sexual activity and appetite. In this way, serotonin (5-hydroxytryptamine, 5-HT) is one of the most attractive targets for medicinal chemists and pharmaceutical companies. Among 5-HTRs, the 5-HT1A subtype is the best studied, and it is generally accepted that it is involved in psychiatric disorders such as anxiety and depression. Several structurally different compounds are known to bind 5-HT1A receptor sites such as aminotetralins, ergolines, arylpiperazines, indolylalkylamines, aporphines and aryloxyalkyl-amines. In this review, we report an overview of the 5-HT1A receptor ligands, belonging to different chemical classes.

An easy and convenient microwave-assisted synthesis of N-alkylated glycine methyl esters is described. Parallel and nonparallel combinatorial methods are described and compared. The described reactions are reductive alkylations of several aldehydes and glycine methyl ester in the presence of NaBH3CN. Good yields and short reaction times are the main aspects of these procedures.

Heterocyclic compounds hold a special place among pharmaceutically important natural and synthetic materials. The remarkable ability of heterocyclic nuclei to serve both as biomimetics and reactive pharmacophores has largely contributed to their unique value as traditional key elements of numerous drugs. In both lead identification and lead optimization processes there is an acute need for new organic small molecules. Traditional methods of organic synthesis are orders of magnitude too slow to satisfy the demand for these compounds. The fields of combinatorial and automated medicinal chemistry have been developed to meet the increasing requirement of new compounds for drug discovery, within these fields, speed is of the essence. The efficiency of microwave flash-heating chemistry in dramatically reducing reaction times (reduced from days and hours to minutes and seconds) has recently been proven in several different fields of organic chemistry. We believe that the time saved by using focused microwaves is potentially important in traditional organic synthesis but could be of even greater importance in high-speed combinatorial and medicinal chemistry. In this review, it is impossible to cover all significant developments in the area of microwave-assisted organic synthesis (MAOS). Rather, outlines the basic principles behind the technology and summarizes the areas in which microwave technology has made an impact, to date. Specific attention is given to application of microwave irradiation in liquid systems, and in the solid state as well of several representative biologically interesting nuclei. In addition we report some of the most recently disclosed applications in combinatorial chemistry.

Protease-activated receptor 2 (PAR-2) is involved in inflammatory, gastrointestinal, and vascular diseases. The aim of the present work was to elucidate the minimal structural features for PAR-2 agonist activity in short peptides. Our study resulted in the discovery of dipeptide derivatives of N α -benzoyl-Arg(NO 2 )-Leu-NH 2 displaying a potency comparable to that of the full-length rat PAR-2 activating peptide (Ser-Leu-Ile-Gly-Arg-Leu-NH 2 ).

As part of a search for new potassium channel openers, the synthesis and vasorelaxant activity of new 1,4-benzoxazines I (R = H, Me, Cl, NO2, CN, D2-thiazolin-2-yl, R1 = H, Me, n = 1, 2) derived from transformation of the benzopyran skeleton of cromakalim (CRK) were described. Several new 1,4-benzoxazines were provided with significant vasorelaxant activity with an overall pharmacol. behavior similar to CRK

This work reports the synthesis by microwave irradiation and the binding tests on the 5-HT(1A), 5-HT(2A) and 5-HT(2C) receptors of new substituted piperazines in order to identify selective ligands for 5-HT(1A) subtype receptor. Conventional heating and microwave irradiation of the reactions was compared. Synthesis by microwave irradiation gave the desired compounds in better yields than those obtained by conventional heating. The overall times for the syntheses were considerably reduced. Some resulting active compounds (29 and 39) were characterised by a good selectivity profile for the 5-HT(1A) subtype receptor. The more active compounds were selected and further evaluated for their binding affinities on D(1), D(2) dopaminergic and alpha(1), alpha(2) adrenergic receptors. The compound with higher affinity and selectivity for the 5-HT(1A) over all the considered receptors was the 3-[4-[4-(1,2,3,4-tetrahydronaphthyl)-1-piperazinyl]butan]-benzotriazinone (-)29 (5-HT(1A) K(i)=36 nM, other receptors not active).

A series of novel 1,2,3-benzotriazin-4-one derivatives was prepared and evaluated as ligands for 5-HT receptors. Radioligand binding assays proved that the majority of the novel compounds behaved as good to excellent ligands at the 5-HT1A receptor, some of which were selective with respect 5-HT2A and 5-HT2C receptors. Six analogues (1a, 2a, 2b, 2c, 2e and 2i) were selected and further evaluated for their binding affinities on D1, D2 dopaminergic and α1-, α2-adrenergic receptors. A o-OCH3 derivative (2e) bound at 5-HT1A sites with subnanomolar affinity (IC50=0.059 nM) and shows high selectivity over all considered receptors and may offer a new lead for the development of therapeutically efficacious agents.

The Dmt-Tic pharmacophore exhibits potent δ-opioid receptor antagonism. Analogues with substitutions in the second pharmacophore with ( 1 , 1 ′) or without a COOH function ( 2 – 9 ) were synthesized: several had high δ affinity ( 1 ′, 2 , 7 , and 9 ), but exhibited low to non-selectivity toward μ receptors similar to H-Dmt-Tic-amide and H-Dmt-Tic-ol. Functional bioactivity indicated high δ antagonism (p A 2 7.4–7.9) ( 1 ′, 2 , and 9 ) and modest μ agonism, pEC 50 (6.1–6.3) ( 1 ′, 2 , 8 , and 9 ), but with E max values analogous to dermorphin. These Dmt-Tic analogues with mixed δ antagonist/μ agonist properties would appear to be better candidates as analgesics than pure μ agonists.

With the aim of discovering new molecules with K + -channel activating properties, we have synthesized derivatives of cromakalim (CRK), an important molecule which shows specific affinity towards K + channels, by replacing the benzopyrane ring of this reference compound with a 1,4-benzoxazine moiety. A different number of substituents showing a good discrimination between hydrophobic and electronic properties have been inserted at the 6-position of the 1,4-benzoxazine ring. We describe here the synthesis and discuss the solid state conformation of these new molecules. When tested on rat aorta ring precontracted with phenylephrine, two compounds ( 2c and 2d ) showed a concentration-dependent relaxation similar to that measured for cromakalim but less potent than this reference drug.

The solid phase procedure, based on the Fmoc chemistry, was used to prepare some opioid deltorphin (H-Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2, DEL C) and dermorphin (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2, DER) analogues in which a D-glucopyranosyl moiety is beta-O-glycosidically linked to a Thr4 or Thr7 side chain. Their activities were determined in binding studies based on displacement of mu- and delta-receptor selective radiolabels from rat brain membrane synaptosomes, in guinea pig ileum and rabbit jejenum bioassays, and, in vivo, by a mouse tail-flick test after intracerebroventricular (icv) and subcutaneous (sc) administrations. The glyco analogues modified at position 4 displayed low opioid properties, while Thr7-glycosylated peptides retained high delta- or mu-selectivity and remarkable activity in vivo. In particular, as systemic antinociceptive agents, the latter glucoside-bearing compounds were more potent than the parent unglycosylated peptide counterparts, showing a high blood to brain rate of influx which may be due to the glucose transporter GLUT-1.

In order to further develop structure–activity relationships and to get information about the biological active conformations we synthetized analogues tripeptide to the FR 113680 [Ac- Thr-D-Trp(CHO)-PheNMeBzl; Ac: acethyl], in which the phenylalanine residue was replaced by unconventional amino acids [1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic); (3aS, 7aS)-octahydroindole-2-carboxylic acid (Oic); (S,S,S)-2-azabiciclo[3.3.0]octane-3-carboxylic acid (Aoc); 3-(1′-naphthyl) alanine (Nap) phenylglicine (Phg); thienylalanine (Thi)]. The biological activity of the peptides was performed on guinea pig ileumfar neurokinin 1 (NK-1) and on rat colon for neurokinin 2 (NK-2). In particular, the replacement of the Phe3 by the Oic (8a) gave an higher antagonist activity in both NK-1 and NK-2 receptors, but no improvement in selectivity with respect to reference tripeptide (FR113680) The compound (8a) represent the first example of highly potent peptides that do not contain an aromatic mi no acid of the third position as had been previously considered essential. © 1995 John Wiley & Sons, Inc.

The crystal structures of the (Z) and (E) geometric isomers of 2-(2-phenylbenzylidene)-3-quinuclidinone were solved by direct methods, using diffractometric data, and refined to final R values of 0.040 and 0.061. The molecules of the (Z) and (E) geometric isomers show trans and cis conformation of the substituents around the double bond, respectively. The quinuclidine and the diphenyl moieties show deformations in their geometric and conformational parameters due to the need of releasing intramolecular strains and/or non-bonded interactions.

Summary This paper outlines the synthesis and the pharmacological screening of a series of novel 1- and 2-[2-[4-(X)-1-piperazinyl] ethyl]benzotriazoles and 1-[3-[4-(X)-1-piperazinyl]propoxy]benzotriazoles, which are structurally related to trazodone. Antiserotonergic, antiadrenergic and antihistaminic in vitro activity and in vivo analgesic action are described. Some of the investigated compounds show overall pharmacological profiles similar to that of the antidepressant trazodone.

A set of 1-methyl-2-(4- X -benzoyl)imidazole-5-acetic acids that are structurally related to tolmetin and zomepirac were synthesized and biologically evaluated for their antiinflammatory activity. The results of in vivo tests and enzymatic assays showed that some of the investigated compounds are characterized by an analgesic-antiinflammatory profile similar or better than that of tolmetin. Preliminary structure-activity relationships suggest that activity is promoted by electron-releasing substituents in the para -position of the benzoyl moiety.