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Malaria is a vector-borne tropical disease caused by protozoans belonging to the genus Plasmodium, which has been scourging mankind for hundreds of millions of years. Despite the masterful progress in preventing disease transmission and reducing morbidity and fatal outcomes, malaria is on the rise again. Global concerns are focused on the spread of resistance to current drugs in the management of severe or ultimately lethal P. falciparum infection. To fully exploit the potential of existing agents and overcome their critical drawbacks, novel synthetic and formulation approaches have been explored. In this field, the clinical value of the natural drug artemisinin (ART) and its derivatives have been firmly established, and ART combination therapies (ACTs) have been recommended as first-line treatment against infection caused by chloroquine-resistant (CQR) P. falciparum strains. Over time, however, ART treatment options have become inadequate, and strict demand for new and effective agents has emerged. In this chapter, the medicinal chemistry aspects of artemisinins will be discussed, covering their unique mode of action and their structural features in relation to stability, pharmacokinetic profile, and antiplasmodial activity. Beyond ACT strategies, significant classes of compounds obtained through both ART covalent bitherapy and dimerization approaches will be presented as well. Furthermore, a special section will focus on the most recent endoperoxide-based synthetic antimalarials as new powerful and cost-effective alternatives to the “golden drug”. It is expected that reported results will provide a strong incentive for further studies, and that unceasing research efforts will succeed in reaching the eventual eradication of this endemic plague.

The protozoan parasite Trypanosoma brucei causes human African trypanosomiasis (HAT), a fatal and neglected disease in the tropic areas. Owing to the scarcity of investments, new drug approvals, and resistance development to the current drugs, novel and selective targets are urgently needed to be explored. Trypanothione reductase, nitro-reductase, pteridine reductase 1, methionyl-tRNA synthetase, phosphodiesterases, and rhodesain represent emerging and attractive enzymes for the development of alternative anti-parasitic agents. The structure-activity relationships for each target were discussed as well as the correlation between in vitro and cell-based assays. These compounds could provide new therapeutic options for the limited arsenal of antitrypanosomal agents and are characterized by a good selectivity profile in terms of cytotoxicity against mammalian cells.

Biofilm is a complex aggregation of microorganisms characterized by the presence of a dynamic, adhesive and protective extracellular matrix composed of polysaccharides, proteins and nucleic acids. It is estimated that the vast majority of human infections are related to the biofilm in which the microorganisms reside and communicate with each other (Quorum Sensing), surviving in hostile environmental conditions.This review provides a comprehensive focus on the development state of promising strategies against biofilm production and eradication describing chemical structures, results, administration routes, pharmaceutical compositions, and SARs as well as their shortcomings within the 2019-2020 range.New pharmacological targets have been explored in the past years, allowing a broader therapeutic arsenal against biofilm-related pathologies. The Quorum Sensing system was targeted as well in order to avoid the development of intrinsically antibiotic-resistant bacteria and to enhance a proper host defense.

In this work we report the application of the ring-closing metathesis (RCM) to the preparation of two cyclic olefin-bridged analogues of biphalin (Tyr-d-Ala-Gly-Phe-NH-NH ← Phe ← Gly ← d-Ala ← Tyr), using the second generation Grubbs' catalyst. The resulting cis- and trans-cyclic isomers were identified, fully characterized, and tested in vitro at μ (ΜΟR), δ (DOR), and κ (KOR) opioid receptors and in vivo for antinociceptive activity. Both were shown to be full agonists at MOR and potential partial antagonists at DOR, with low potency KOR agonism. They also share a strong antinociceptive effect after intracerebroventricular (i.c.v.) and intravenous (i.v.) administration, higher than that of the cyclic biphalin analogues containing a disulfide bridge between the side chains of two d-Cys or d-Pen residues, previously described by our group.

Pancreatic lipase (PL) is a key enzyme for the degradation of triglycerides absorbed in the diet and it is involved in several pathologies, such as acute pancreatitis, an inflammatory state of the pancreas. In this work we performed the virtual screening of a tripeptide library, with the aim to discover novel lead compounds as inhibitors of human PL. The 9 top-ranked peptides were synthesized by solid phase peptide synthesis and tested in vitro. Among them, peptides M5 and M7 were found to be the most potent inhibitors of the series, validating our method as a useful strategy to discover peptide inhibitors.

WOS: 000456314600016, Several plants belonging to the genus Capparis are the focus of growing interest due to their singular nutritional and medicinal properties. In the present study, flower bud samples from C. spinosa L. (Lipari Island, Italy) were subjected to decoction, Soxhlet, and microwave extraction techniques and the individual extracts investigated to better characterize the phytochemical and antioxidant profiles of the plant. Total phenolic and flavonoid amounts, phenolic composition, radical scavenging as well as reductive and metal chelating properties were determinated by well-established chemical and analytical procedures. Furthermore, cholinesterase inhibitory effects were evaluated by Ellman's method. Fatty acid percentage and essential oil composition were also detected by GC and GC-MS techniques respectively. Rutin was found to be the major component in the studied extracts. The Soxhlet extract exhibited the strongest radical scavenging and reductive activities as compared to the other extracts, most probably due to the highest concentration of phenolics, especially rutin. The best cholinesterase inhibitory effect was observed in the microwave extract. Palmitic acid was the most abundant fatty acid in the studied oil, whereas docosane was the major volatile compound in the essential oil. Present data corroborate the multipurpose potential of C. spinosa for designing bio-based drug formulations or functional applications. (c) 2018 SAAB. Published by Elsevier B.V. All rights reserved.

Malaria is a mosquito-borne infectious disease caused by Plasmodium spp. It has severely impacted on individual and community productivity, social behavior, urbanization, as well as cultural, political, and economic developments in countries, where it is endemic. Given the high efficacy of major antimalarial drugs in targeting different stages of the parasite life cycle and the access to prophylactic measures, malaria was near to be eradicated. However, the emergence of resistance by parasites towards both curative and preventive drugs, and by mosquitoes to insecticides and traps has reopened the challenge. Natural products are still considered by the global medical researchers as a rich source of new chemical entities for the development of safe, cheap, and sustainable therapeutic agents. Natural products have been the mainstay of antimalarial therapy for thousands of years, and some are used in the traditional medicine by local populations, where malaria is endemic. This chapter updates the recent discoveries in phytochemical remedies that are able to treat malaria at different stages (prevention, recurrence, and therapy) as a result of limitations of synthetic drugs. These active compounds are organized according to their plants and fungi families. This in-depth survey attempts to analyze not only plant extracts, but also their main component’s bioactivity, the mechanism of action, and the potential synergism with other known drugs and side effects. Medicinal chemists can take advantage of such scaffolds to derive semisynthetic compounds with improved pharmacodynamic and pharmacokinetic properties. It is important that the efficacy and safety of traditional medicines must be validated, and their active constituents should be identified to establish reliable structure activity relationships.

Matrix metalloproteinases (MMPs) are a large family of zinc-dependent endoproteases known to exert multiple regulatory roles in tumor progression and invasiveness. This encouraged over the years the approach of MMP, and particularly MMP-2, targeting for anticancer treatment. Early generations of MMP inhibitors, based on aspecific zinc binding groups (ZBGs) assembled on (pseudo)peptide scaffolds, have been discontinued due to the clinical emergence of toxicity and further drawbacks, giving the way to inhibitors with alternative zinc-chelator moieties or not binding the catalytic zinc ion. In the present paper, we continue the search for new non-zinc binding MMP-2 inhibitors: exploiting previously identified compounds, a virtual screening (VS) campaign was carried out and led to the identification of a new class of ligands. The structure-activity relationship (SAR) of the benzimidazole scaffold was explored by synthesis of several analogues whose inhibition activity was tested with enzyme inhibition assays. By performing the molecular simplification approach, we disclosed different sets of single-digit micromolar inhibitors of MMP-2, with up to a ten-fold increase in inhibitory activity and ameliorated selectivity towards off-target MMP-8, compared to selected lead compound. Molecular dynamics calculations conducted on complexes of MMP-2 with docked privileged structures confirmed that analyzed inhibitors avoid targeting the zinc ion and dip inside the S1′ pocket. Present results provide a further enrichment of our insights for the design of novel MMP-2 selective inhibitors.

Aim: The inhibition of pancreatic lipase (PL) represents one of the most promising strategies in the search for novel antiobesity drugs. We propose here a pioneering course by exploring tripeptide scaffolds in the way to selective PL inhibitors. Methodology/Results: The peptide series exhibited good PL inhibitory properties in vitro, with all the strongest inhibitors sharing a central arginine, shown in silico to be relevant for the active site-directed activity. The compounds were found devoid of inhibitory properties on acetylcholinesterase. Conclusion: Present results disclosed that basic tripeptides are able to interact efficiently with the PL-binding pocket, where they adopt a binding pose suitable for functional-to-inhibition interactions with key amino acids. Main inhibitor MALA4 may be selected as lead for further optimization.

[Image: see text] In this work we report the application of the ring-closing metathesis (RCM) to the preparation of two cyclic olefin-bridged analogues of biphalin (Tyr-d-Ala-Gly-Phe-NH-NH ← Phe ← Gly ← d-Ala ← Tyr), using the second generation Grubbs’ catalyst. The resulting cis- and trans-cyclic isomers were identified, fully characterized, and tested in vitro at μ (ΜΟR), δ (DOR), and κ (KOR) opioid receptors and in vivo for antinociceptive activity. Both were shown to be full agonists at MOR and potential partial antagonists at DOR, with low potency KOR agonism. They also share a strong antinociceptive effect after intracerebroventricular (i.c.v.) and intravenous (i.v.) administration, higher than that of the cyclic biphalin analogues containing a disulfide bridge between the side chains of two d-Cys or d-Pen residues, previously described by our group.

The endogenous ligand nociceptin (N/OFQ) and a positively charged synthetic peptide RYYRIK are both selective for the nociceptin opioid receptor (NOPr). Despite their structural dissimilarity, N/OFQ and RYYRIK compete for the same binding site of NOP receptor possessing full and partial agonistic character, respectively. In the view of the message-address concept, hybrid peptide constructs were probed for the NOP receptor combining different regions of N/OFQ and RYYRIK related peptide sequences. Nine novel nociceptin- or Ac-RYYRIK-NH2 peptide variants or hybrid peptides were synthesized and characterized. Peptides P2 and P8 contain fragments of native N/OFQ. The other seven analogues (P1, P3-7, P9) are composed of Ac-RYYRIK-NH2 fragments and parts of the original nociceptin sequence. The analogues were characterized in receptor binding assays and G-protein activation experiments on rat brain membranes, as well as by electrically stimulated mouse vas deferens bioassay. In receptor binding assays ligands P2, P4, P6 (Ki 0.37 nM) and P7 showed higher affinity (Ki 0.65 nM, 0.6 nM, 0.37 nM and 0.44 nM, respectively) for NOP receptor than their parent compounds N/OFQ (Ki 2.8 nM) or Ac-RYYRIK-NH2 (Ki 4.2 nM). In [35S]GTPγS binding experiments P2 and P3 behaved as full agonists. The other variants exhibited partial agonist properties characterized by submaximal stimulatory effects. In mouse vas deferens bioassay only P2 showed agonist activity. P4, P5, P6 inhibited the biological activity of N/OFQ more effectively than the NOP receptor selective antagonist JTC-801. In summary, hybrid peptides P4, P5 and P6 proved to be NOP receptor partial agonists even antagonists, while P2 peptide retained the full agonist property.

Crocus sativus L. is known in herbal medicine for the various pharmacological effects of its components, but no data are found in literature about its biological properties toward Helicobacter pylori, Plasmodium spp. and Leishmania spp. In this work, the potential anti-bacterial and anti-parasitic effects of crocin and safranal, two important bioactive components in C. sativus, were explored, and also some semi-synthetic derivatives of safranal were tested in order to establish which modifications in the chemical structure could improve the biological activity. According to our promising results, we virtually screened our compounds by means of molecular modeling studies against the main H. pylori enzymes in order to unravel their putative mechanism of action.

A series of nanomolar phosphonate matrix metalloproteinase (MPP) inhibitors was tested for inhibitory activity against a panel of selected human carbonic anhydrase (CA, EC 4.2.1.1) isozymes, covering the cancer-associated CA IX and XII. None of the reported sulfonyl and sulfonylamino-derivatives sensitively affected the catalytic activity of the cytosolic isoforms CA I and II, which are considered off-target isoforms in view of their physiological role. The most active inhibitors were in the series of chiral N-(sulfonyl)phosphovaline derivatives, which showed good to excellent inhibitory activity over target CAs, with compound 15 presenting the best isoform-selectivity toward CA IX. We suggest here that the phosphonates have the potential as dual inhibitors of MMPs and CAs, both involved in tumor formation, invasion and metastasis.

Aim: The conjugation of fluorescent labels to opioid peptides is an extremely challenging task, which needs to be overcome to create new classes of probes for biological assays. Materials & methods: Three opioid peptide analogs of biphalin and [D-Pen2,5]-Enkephalin (DPDPE) containing a fluorescein–maleimide motif were synthesized. Results & discussion: The biphalin analog 17 binds to opioid receptors with Ki μ = 530 ± 90 nM and Ki δ = 69.8 ± 16.4 nM. We then tested the ability of the compounds to stimulate G-protein-coupling, 17 activated μ-receptor expressing cells (EC50 = 16.7 ± 6.7 nM, EMax = 76 ± 4%) as well as δ-receptor expressing cells (EC50 = 42 ± 10 nM, EMax = 34 ± 8%). However, 17 was not able to fluorescently label receptor in live or fixed cells. Conclusion: Our data suggest that the biphalin scaffold could be employed to develop fluorescent ligands with the appropriate fluorescent motif, and suggest a means for further probe development.

Endomorphin-2 [Tyr-Pro-Phe-Phe-NH2] and DAMGO [Tyr-D-Ala-Gly-(N-Me)Phe-Gly-ol] are natural (EM2) and synthetic (DAMGO) opioid peptides both selective for μ opioid receptor with high analgesic activity. In this work we report synthesis, in vitro and in vivo biological evaluation of five new hybrid EM2/DAMGO analogues, with the aim to obtain compounds with high affinity at μ-opioid receptor, high activity in animal nociception tests (hot plate and tail flick) and improved enzymatic stability. Double N-methylation on both Phe residues and C-terminal ethanolamide led to analogue 6e, which possesses a good in vitro μ affinity (Kiμ=34 nM), combined with a remarkable in vivo antinociceptive activity.

Caspase-3 is responsible for the cleavage of several proteins including the nuclear enzyme poly(ADP-ribose) polymerase (PARP). Designed on the cleavage site of PARP, Ac-Asp-Glu-Val-Asp-H has been reported as a highly specific inhibitor. To overcome the susceptibility to proteolysis, the intrinsic instability, and the scarce membrane permeability of tetra-peptidyl aldehydes, di- and tri-peptidyl caspase-3 inhibitors have been synthesized. Here, the synthesis and the inhibition properties of peptidyl aldehydes Z- t Leu-Asp-H, Z- t Leu-Val-Asp-H, and Z-Val- t Leu-Asp-H are reported. Z- t Leu-Asp-H, Z- t Leu-Val-Asp-H, and Z-Val- t Leu-Asp-H inhibit competitively human caspase-3 activity in vitro with K i 0 = 3.6 nM, 18.2 nM, and 109 nM, respectively (pH 7.4 and 25 °C). Moreover, Z- t Leu-Asp-H impairs apoptosis in human DLD-1 colon adenocarcinoma cells without affecting caspase-8. Therefore, Ac-Asp-Glu-Val-Asp-H can be truncated to Z- t Leu-Asp-H retaining nanomolar inhibitory activity in vitro and displaying action in whole cells, these properties reflect the unprecedented introduction of the bulky and lipophilic t Leu residue at the P 2 position.

The fully deprotected glutathione analogue containing the aminomethylene unit as transition state isostere of the gamma-Glu-Cys peptide bond was synthesized for the first time and characterized in both the reduced and oxidized forms.

The TRH analogue 3, incorporating the (S)-isothiazolidine-1,1-dioxide-3-carboxylic acid (1) moiety in place of the native L-pyroglutamic acid (pGlu) residue, has been synthesized and fully characterized by 1H and 13C NMR. The effects of replacing pGlu with its sulphonamido counterpart on biological activity have been investigated. This peptide, which is significantly stabilized towards hydrolysis by pyroglutamyl peptidase type I (PP I, EC 3.4.19.3), has shown to maintain in vitro prolactin-releasing activity.

This paper reports the synthesis of tauryl dipeptides related to carnosine. In particular H-Tau-His-OH (5), H-Tau-His(π-Me)-OH (6) and H-Tau-His(τ-Me)-OH (9) are described. The enzyme carnosinase has been isolated from pig kidney and after purification has been used to test the stability and the inhibitory activity of the three new analogues. H-Tau-His-OH (5) and H-Tau-His(τ-Me)-OH (9) were found to possess weak inhibitory properties towards carnosinase, while H-Tau-His(π-Me)-OH (6) proved to be devoid of any significant activity. All the three sulfonamido pseudopeptides 5, 6 and 9 show stability to carnosinase activity.

Caspase-3 displays a pivotal role as an executioner of apoptosis, hydrolyzing several proteins including the nuclear enzyme poly(ADP-ribose)polymerase (PARP). Ac-Asp-Glu-Val-Asp-H (K (i)A degrees A = 2.3 x 10(-10) M at pH 7.5 and 25.0 A degrees C), designed on the basis of the cleavage site of PARP, has been reported as a highly specific human caspase-3 inhibitor. Here, di- and tri-peptidyl aldehydes 11-13 and 27-29 have been synthesized to overcome the susceptibility to proteolysis, the intrinsic instability, and the scarce membrane permeability of the current inhibitors. Compounds 11-13, 27-29 inhibit in vitro human caspase-3 competitively, values of K (i)A degrees ranging between 6.5 (+/- 0.82) x 10(-9) M and 1.1 (+/- 0.04) x 10(-7) M (at pH 7.4 and 25.0 A degrees C). Moreover, the most effective caspase-3 inhibitor 11 impairs apoptosis in human DLD-1 colon adenocarcinoma cells. Furthermore, the binding mode of 11-13 and 27-29 to human caspase-3 has been investigated in silico. The comparative analysis of human caspase-3 inhibitors indicates that (1) aldehyde 11 is the minimal highly effective inhibitor, (2) the tLeu-Asp sequence is pivotal for satisfactory enzyme inhibition, and (3) the occurrence of the tLeu residue at the inhibitor P2 position is fundamental for enzyme/inhibitor recognition. Moreover, calculations suggest that the tLeu residue reduces the conformational flexibility of the inhibitor that binds to the enzyme with a lower energetic penalty.

In the context of a research program aimed at synthesizing pseudopeptidic ergopeptines, the incorporation of an α-azaPhe residue into the peptidic moiety of ergotamine has been studied. Acylation of cyclo(-azaPhe-Pro-) 6 with (+)-(S)-2-benzyloxy-2-methylmalonyl monoethyl ester monochloride 5 gives the (E)-isoimide 7 as the predominant reaction product; contrary to expectation the conversion of 7 into the desired imide isomer 8 proceeds with difficulty and is accompanied by decomposition. Hydrogenolysis of 8 leads stereospecifically to the pseudopeptidic oxa-cyclol ethyl ester 9. Subsequent rearrangement of the corresponding oxa-cyclol acyl-azide 11 in the presence of benzyl alcohol fails to give the pseudopeptidic ergotamine oxa-cyclol. The new stable pseudopeptidic aza-cyclol 12 containing the residue of the didehydroalanine has been isolated together with a comparable amount of the imino aza-cyclol derivative 13. The mechanism of the formation of the new products 12 and 13 and the unexpected stability of the (E)-isoimide 7 are discussed.

As part of a programme to synthesize pseudopeptidic ergopeptines, the introduction of an α-azaproline residue in place of native proline into an ergotamine-like oxacyclolic system has been investigated. Starting material N-[(R)-2- benzyloxypropionyl]cyclo(-Phe-azaPro-)10 was prepared following two alternative synthetic routes and was subjected to reductive O-debenzylation. N,O-Acyl transfer on the resulting N-[(R)-2-hydroxypropionyl]cyclo(Phe-azaPro-)14 leads, through a new type of four- heteroatom tetrahedral adduct, to (5R)-5-methyl-3-{(1S)-2-phenyl-1-[(pyrazolidin-1-yl)carbonyl]ethyl}oxazolidine-2,4-dione 16, as a unique isolable tautomer. Structural and conformational details of compound 14, as revealed by X-ray analysis, are reported and compared with those of previously studied related models.

This review reports recent structural modifications (since 1989) performed on the glutathione molecule both in the oxidized and reduced form. Relevant chemical aspects, biochemical consequences and therapeutical implications are illustrated. Natural thiols related to glutathione are also considered 1 .

Elevated levels of glutathione S-transferases (GSTs) are among the factors associated with an increased resistance of tumors to a variety of antineoplastic drugs. Hence a major advancement to overcome GST-mediated detoxification of antineoplastic drugs is the development of GST inhibitors. Two such agents have been synthesized and tested on the human Alpha, Mu and Pi GST classes, which are the most representative targets for inhibitor design. The novel fluorescent glutathione S-conjugate L-gamma-glutamyl-(S-9-fluorenylmethyl)-L-cysteinyl-glycine (4) has been found to be a highly potent inhibitor of human GSTA1-1 in vitro (IC50=0.11+/-0.01 microM). The peptide is also able to inhibit GSTP1-1 and GSTM2-2 isoenzymes efficiently. The backbone-modified analog L-gamma-(gamma-oxa)glutamyl-(S-9-fluorenylmethyl)-L-cysteinyl-glycine (6), containing an urethanic junction as isosteric replacement of the gamma-glutamyl-cysteine peptide bond, has been developed as gamma-glutamyl transpeptidase-resistant mimic of 4 and evaluated in the same inhibition tests. The pseudopeptide 6 was shown to inhibit the GSTA1-1 protein, albeit to a lesser extent than the lead compound, with no effect on the activity of the isoenzymes belonging to the Mu and Pi classes. The comparative loss in biological activity consequent to the isosteric change confirms that the gamma-glutamyl moiety plays an important role in modulating the affinity of the ligands addressed to interact with GSH-dependent proteins. The new specific inhibitors may have a potential in counteracting tumor-protective effects depending upon GSTA1-1 activity.

The new GSH analogues H–Glo(–Ser–Gly–OH)–OH ( 5 ), its O -benzyl derivative 4 , and H–Glo(–Asp–Gly–OH)–OH ( 9 ), characterized by the replacement of central cysteine with either serine or aspartic acid, and containing an urethanic fragment as isosteric substitution of the scissile γ-glutamylic junction, have been synthesized and characterized. Their ability to inhibit human GST P1-1 (hGST P1-1) in comparison with H–Glu(–Ser–Gly–OH)–OH and H–Glu(–Asp–Gly–OH)–OH, which are potent competitive inhibitors of rat GST 3-3 and 4-4, has been evaluated. In order to further investigate the effect of the isosteric substitution on the binding abilities of the new GSH analogues 4 , 5 and 9 , the previously reported cysteinyl-containing analogue H–Glo(–Cys–Gly–OH)–OH has been also evaluated as a co-substrate for hGSTP1-1.

A series of 5-hydroxy- and 5,6-dihydroxy-1,2,3,7,12,12a-hexahydrobenzo[5,6]cyclohepta[1,2,3-ij]isoquinoline derivatives (5a--e and 6a--e) were synthesized as conformationally rigid analogues of 1-benzyltetrahydroisoquinoline and evaluated for their affinity at D(1) and D(2) dopamine receptors. All compounds showed lower D(1) and D(2) affinities than dopamine. The 5-hydroxy-1-methyl-2,3,12,12a-hexahydrobenzo[5,6]cyclohepta[1,2,3-ij]isoquinoline 5a and the 5,6-dihydroxy analogue 6a showed D(2) agonist activity. This was proved by their effects on prolactin release from primary cultures of rat anterior pituitary cells. Molecular modeling studies showed that the geometric parameters (namely the distances from meta and para hydroxyl oxygens to the nitrogen and the height of nitrogen from the hydroxylated phenyl ring plane) of the dopaminergic pharmacophore embedded in our compounds have lower values in comparison with those observed in D(1) and D(2) selective ligands.

This review reports recent structural modifications (since 1989) performed on the glutathione molecule both in the oxidized and reduced form. Relevant chemical aspects, biochemical consequences and therapeutical implications are illustrated. Natural thiols related to glutathione are also considered 1 .

Background A detailed comprehension of central mechanisms underlying feeding behavior holds considerable promise for the treatment of alimentary disorders Methods In order to elucidate the tight interrelationships occurring at the hypothalamic neuronal endings between aminergic neurotransmitters and co-localized appetite modulators, we initially studied the effects of two anorexigenic peptides structurally related to thyrotropin-releasing hormone (TRH, 1 ), namely cyclo(His-Pro) (CHP, 2 ) and pGlu-His-Gly-OH ( 3 ), on [ 3 H]-norepinephrine and [ 3 H]-dopamine release from perfused rat hypothalamic synaptosomes. Furthermore, a number of TRH and CHP analogues were synthesized and tested for their ability to influence neurotransmitter release in the selected neuronal model Results Peptide 3 showed only a slight inhibitory activity on norepinephrine release, whereas no effect was observed for compound 2 . TRH analogue 8 , metabolically stabilized by the replacement of pyroglutamate with the pyrohomocysteic acid (pHcs), was found to be inactive. Conversely, a significant inhibitory effect on dopamine and norepinephrine release was observed for the CHP-related diketopiperazines cyclo(Leu-Pro) ( 11 ) and cyclo(His-Gly) ( 14 ) Conclusions These results suggest a potential role for cyclo-dipeptides 11 and 14 in the hypothalamic modulation of appetite suppressant circuitry