Salvatore Vomero

Evaluation of three quinoline-carboxamide derivatives as potential radioligands for the in vivo pet imaging of neurodegeneration.

The peripheral-type benzodiazepine receptors (PBRs) are only minimally expressed in normal brain parenchyma, where they are primarily localized in glial cells. Their basal expression rises in different neurodegenerative disorders, due to the presence of infiltrating inflammatory cells and activated microglia. [11C]PK11195, a selective PBR antagonist, has been used for the in vivo PET monitoring of neurodegeneration in clinical observations. We recently developed and labeled with carbon-11 three new carboxamide derivatives: [11C]VC193M, [11C]VC195 and [11C]VC198M. Aim of this study was to evaluate these ligands for the in vivo measuring of PBRs expression in neurodegenerations and compare their kinetic behavior with that of the reference tracer [11C]PK11195. Radioligands were evaluated in a preclinical model of Huntingtons disease consisting in the monolateral striatal injection of quinolinic acid (QA). Activated microglia and astrocytic gliosis was present only within the affected striatum. A concomitant increase in radioactivity accumulation was observed for all the tracers examined (P<0.01). Among the new compounds, [11C]VC195 showed higher levels of lesioned/unlesioned striatum ratios (3.28+/-0.44), in comparison with [11C]VC193M and [11C]VC198M (2.69+/-0.53 and 1.52+/-0.36, respectively), but slightly inferior to that observed for [11C]PK11195 (3.76+/-1.41).In conclusion, the results of the study indicate that [11C]VC195 is a promising candidate for in vivo PET monitoring of neurodegenerative processes but its in vivo behavior overlap that of [11C]PK11195.

Multivalent supramolecular dendrimer-based drugs

Supramolecular complexes consisting of a hydrophobic dendrimer host [DAB-dendr-(NHCONH-Ad)(64)] as well as solubilizing and bioactive guest molecules have been synthesized using a noncovalent approach. The guest-host supramolecular assembly is first preassembled in chloroform and transferred via the neat phase to aqueous solution. The bioactive guest molecules can bind to a natural (serotonin 5-HT(3)) receptor with nanomolar affinity as well as to the synthetic dendrimer receptor in aqueous solution, going toward a dynamic multivalent supramolecular construct capable of adapting itself to a multimeric receptor motif.

Design, Synthesis, and Biological Evaluation of AT1 Angiotensin II Receptor Antagonists Based on the Pyrazolo[3,4-b]pyridine and related Heteroaromatic Bicyclic Systems

Novel AT 1 receptor antagonists bearing the pyrazolo[3,4- b]pyridine bicyclic heteroaromatic system (or structurally related moieties) were designed and synthesized as the final step of a large program devoted to the development of new antihypertensive agents and to the understanding of the molecular basis of their pharmacodynamic and pharmacokinetic properties. The preliminary pharmacological characterization revealed nanomolar AT 1 receptor affinity for several compounds of the series and a potent antagonistic activity in isolated rabbit aortic strip functional assay for 7c and 8a. These results stimulated the study of the biopharmaceutical properties of some selected compounds, which were found to be characterized by a permeability from medium to high. Remarkably, the least permeable 7c showed both permeability and oral bioavailability (80%) higher than losartan, but its terminal half-life was shorter. These results suggest that the permeability is not a limiting factor in the pharmacokinetics of these AT 1 receptor antagonists.

Synthesis and biological evaluation of amidine, guanidine, and thiourea derivatives of 2-amino(6-trifluoromethoxy)benzothiazole as neuroprotective agents potentially useful in brain diseases.

A series of amidine, thiourea, and guanidine derivatives of 2-amino-6-(trifluoromethoxy)benzothiazole termed 2, 3, and 4, respectively, and structurally related to riluzole, a neuroprotective drug in many animal models of brain disease, have been synthesized. The biological activity of compounds 2a-e, 3a-f, and 4a,b was preliminarily tested by means of an in vitro protocol of ischemia/reperfusion injury. The results demonstrated that 2c and 3a-d significantly attenuated neuronal injury. Selected for testing of their antioxidant properties, compounds 3a-d were shown to be endowed with a direct ROS scavenging activity. Compounds 3b and 3d were also evaluated for their activity on voltage-dependent Na(+) and Ca(2+) currents in neurons from rat piriform cortex. At 50 microM, compound 3b inhibited the transient Na(+) current to a much smaller extent than riluzole, whereas 3d was almost completely ineffective.

Synthesis, biological evaluation, and enzyme docking simulations of 1,5-diarylpyrrole-3-alkoxyethyl ethers as selective cyclooxygenase-2 inhibitors endowed with anti-inflammatory and antinociceptive activity.

A series of substituted 1,5-diarylpyrrole-3-alkoxyethyl ethers (6, 7, and 8) has been synthesized with the aim to assess if in the previously reported 1,5-diarylpyrrole derivatives (5) the replacement of the acetic ester moiety with an alkoxyethyl group still led to new, highly selective and potent COX-2 inhibitors. In the in vitro cell culture assay, all the compounds proved to be potent and selective COX-2 inhibitors. In the human whole blood (HWB) assay, compound 8a had a comparable COX-2 selectivity to valdecoxib, while it was more selective than celecoxib but less selective than rofecoxib. The potential anti-inflammatory and antinociceptive activities of compounds 7a, 8a, and 8d were evaluated in vivo, where they showed a very good activity against both carrageenan-induced hyperalgesia and edema in the rat paw test. In the abdominal constriction test compound 7a, 8a, and 8d were able to reduce the number of writhes in a statistically significant manner. Furthermore, the affinity data of these compounds have been rationalized through enzyme docking simulations in terms of interactions with a crystallographic model of the COX-2 binding site by means of the software package Autodock 3.0.5, GRID 21, and MacroModel 8.5 using the complex between COX-2 and SC-558 (1b), refined at a 3 A resolution (Brookhaven Protein Data Bank entry: 6cox ).

New insight into the central benzodiazepine receptor-ligand interactions: design, synthesis, biological evaluation, and molecular modeling of 3-substituted 6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepines and related compounds.

3-Substituted 6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepines and related compounds were synthesized as central benzodiazepine receptor (CBR) ligands. Most of the compounds showed high affinity for bovine and human CBR, their K(i) values spanning from the low nanomolar to the submicromolar range. In particular, imidazoester 5f was able to promote a massive flow of (36)Cl(-) in rat cerebrocortical synaptoneurosomes overlapping its efficacy profile with that of a typical full agonist. Compound 5f was then examined in mice for its pharmacological effects where it proved to be a safe anxiolytic agent devoid of the unpleasant myorelaxant and amnesic effects of the classical 1,4-benzodiazepines. Moreover, the selectivity of some selected compounds has been assessed in recombinant α(1)β(2)γ(2)L, α(2)β(1)γ(2)L, and α(5)β(2)γ(2)L human GABA(A) receptors. Finally, some compounds were submitted to molecular docking calculations along with molecular dynamics simulations in the Cromers GABA(A) homology model.

Novel Potent 5-HT3 Receptor Ligands Based on the Pyrrolidone Structure: Synthesis, Biological Evaluation, and Computational Rationalization of the Ligand–Receptor Interaction Modalities

Novel conformationally constrained derivatives of classical 5-HT(3) receptor antagonists were designed and synthesized with the aim of probing the central 5-HT(3) receptor recognition site in a systematic way. The newly-synthesized compounds were tested for their potential ability to inhibit [(3)H]granisetron specific binding to 5-HT(3) receptor in rat cortical membranes. These studies revealed subnanomolar affinity in some of the compounds under study. The most potent ligand in this series was found to be quinuclidine derivative (S)-7i, which showed an affinity comparable with that of the reference ligand granisetron. The potential 5-HT(3) agonist/antagonist activity of some selected compounds was assessed in vitro on the 5-HT(3) receptor-dependent [(14)C]guanidinium uptake in NG 108-15 cells. Both of the tropane derivatives tested in this functional assay (7a and 9a) showed antagonist properties, while the quinuclidine derivatives studied [the enantiomers of compounds 7i, 8g, and 9g, and compound (R)-8h] showed a full range of intrinsic efficacies. Therefore, the functional behavior of these 5-HT(3) receptor ligands appears to be affected by the structural features of both the azabicyclo moiety and the heteroaromatic portion. In agreement with the data obtained on NG 108-15 cells, investigations on the 5-HT(3) receptor-dependent Bezold-Jarisch reflex in urethane-anaesthetized rats confirmed the 5-HT(3) receptor antagonist properties of compounds 7a and (S)-7i showing for these compounds ID(50) values of 2.8 and 181 microg/kg, respectively. Finally, compounds 7a, (S)-7i and 9a (at the doses of 0.01, 1.0, and 0.01 mg/kg ip, respectively) prevented scopolamine-induced amnesia in the mouse passive avoidance test suggestive of a potential usefulness in cognitive disorders for these compounds. Qualitative and quantitative structure-affinity relationship studies were carried out by means of theoretical descriptors derived on a single structure and ad-hoc defined size and shape descriptors (indirect approach). The results showed to be useful in capturing information relevant to ligand-receptor interaction. Additional information derived by the analysis of the energy minimized 3-D structures of the ligand-receptor complexes (direct approach) suggested interesting mechanistic and methodological considerations on the binding mode multiplicity at the 5-HT(3) receptors and on the degree of tolerance allowed in the alignment of molecules for the indirect approach, respectively.

Design, synthesis, and structure–affinity relationship studies in NK1 receptor ligands based on azole-fused quinolinecarboxamide moieties

The substituent in position 2 of the quinoline nucleus of NK(1) receptor ligands 5 has been constrained into different five-membered heterocyclic moieties in order to obtain information on the binding site pocket interacting with this apparently critical portion of ligands 5. This structure-affinity relationship study led to the discovery of novel tricyclic NK(1) receptor ligands 6 showing affinity in the nanomolar range to the sub-micromolar one. The systematic structure variation suggests that electronic features of the tricyclic moiety play a role in modulating the interaction of these amide derivatives with their receptor.

The Interactions of the 5-HT3 Receptor with Arylpiperazine, Tropane, and Quinuclidine Ligands

The serotonin 5-HT(3) receptor subtype is unique among the receptors for this neurotransmitter because it has been demonstrated to be a ligand-gated ion channel capable of mediating rapid intercellular communication. This review covers the authors work performed during more than a decade in the development of 5-HT(3) receptor ligands belonging to the classes of arylpiperazines, tropanes, and quinuclidine derivatives. The discussion is focused mainly on what the authors have learned about the interaction of these structurally different ligands with their receptor and shows the way their ideas evolved along with the progress of the project. Furthermore, a summary of the most significant structure-affinity relationships, derived from the original work, is reported to support the discussion.

NOVEL ANALGESIC/ANTI-INFLAMMATORY AGENTS: 1,5-DIARYLPYRROLE NITROOXYALKYL ETHERS AND RELATED COMPOUNDS AS CYCLOOXYGENASE-2 INHIBITING NITRIC OXIDE DONORS

A series of 3-substituted 1,5-diarylpyrroles bearing a nitrooxyalkyl side chain linked to different spacers were designed. New classes of pyrrole-derived nitrooxyalkyl inverse esters, carbonates, and ethers (7-10) as COX-2 selective inhibitors and NO donors were synthesized and are herein reported. By taking into account the metabolic conversion of nitrooxyalkyl ethers (9, 10) into corresponding alcohols, derivatives 17 and 18 were also studied. Nitrooxy derivatives showed NO-dependent vasorelaxing properties, while most of the compounds proved to be very potent and selective COX-2 inhibitors in in vitro experimental models. Further in vivo studies on compounds 9a,c and 17a highlighted good anti-inflammatory and antinociceptive activities. Compound 9c was able to inhibit glycosaminoglycan (GAG) release induced by interleukin-1β (IL-1β), showing cartilage protective properties. Finally, molecular modeling and (1)H- and (13)C-NMR studies performed on compounds 6c,d, 9c, and 10b allowed the right conformation of nitrooxyalkyl ester and ether side chain of these molecules within the COX-2 active site to be assessed.