Maria Michela Curzu

Synthesis and dopamine D2-like receptor binding affinity of substituted 5-phenyl-pyrrole-3-carboxamides

A series of 5-p-substituted phenyl-pyrrole-3-carboxamide derivatives was designed as hybrid analogs of the dopamine D2-like 5-phenyl-pyrrole and heterocyclic carboxamide antipsychotics. The title compounds were synthesized and evaluated for dopamine D2-like receptor by means of [3H]YM-09151-2 receptor binding assay. The compound bearing a 1-ethyl-2-methyl-pyrrolidine moiety as the basic part of 5-phenyl-pyrrole-3-carboxamide derivative 1a together with its 2-chloro analog 1f were found to possess affinity in the low micromolar range. Substituted phenyl-pyrrolecarboxamides containing groups such as F, Cl, NO2, CH3, at the 4-position of the phenyl ring, gave ligands with lower D2-like affinity.

Synthesis, modelling, and μ-opioid receptor affinity of N-3(9)-arylpropenyl-N-9(3)-propionyl-3,9-diazabicyclo[3.3.1]nonanes

Abstract A series of N -3-arylpropenyl- N -9-propionyl-3,9-diazabicyclo[3.3.1]nonanes ( 1a–g ) and of reverted N -3-propionyl- N -9-arylpropenyl isomers ( 2a–g ), as homologues of the previously reported analgesic 3,8-diazabicyclo[3.2.1]octanes ( I–II ), were synthesized and evaluated for the binding affinity towards opioid receptor subtypes μ, δ and κ. Compounds 1a–g and 2a–g exhibited a strong selective μ-affinity with K i values in the nanomolar range, which favourably compared with those of I and II . In addition, contrary to the trend observed for DBO -I , II , the μ-affinity of series 2 is markedly higher than that of the isomeric series 1 . This aspect was discussed on the basis of the conformational studies performed on DBN which allowed hypotheses on the mode of interaction of these compounds with the μ receptor.

Synthesis of 3,6-diazabicyclo[3.1.1]heptanes as novel ligands for neuronal nicotinic acetylcholine receptors.

Alpha series of novel 3,6-diazabicyclo[3.1.1]heptane derivatives 4a-f was synthesized and their affinity and selectivity towards alpha4beta2 and alpha7 nAChR subtypes were evaluated. The results of the current study revealed a number of compounds (4a, 4b and 4c) having a very high affinity for alpha4beta2 (K(i) at alpha4beta2 ranging from 0.023 to 0.056 nM) versus alpha7 nAChR subtypes; among these compounds, the 3-(6-bromopyridin-3-yl)-3,6-diazabicyclo[3.1.1]heptane 4c was found to be the most alpha7alpha4beta2 selective term in receptor binding assays (alpha7alpha4beta2=1295). Moreover, compound 4d also had high affinity for the alpha4beta2 nAChR subtype (K(i)=1.2 nM) with considerably high selectivity (alpha7/alpha4beta2=23300).

Preparation of Thieno[3,2-h]cinnolinones as Matrix Metalloproteinase Inhibitors

A new series of thieno[3,2‐h]cinnolinone analogues was synthesized which is structurally related to 2,3,4,4a,5,6‐hexahydrothieno[3,2‐h]cinnolin‐3‐one 1, a weak inhibitor of the matrix metalloproteinase MMP‐8 (human neutrophil collagenase). Preliminary SAR studies have shown that while C4a‐methyl, C7‐acetylamino, C7 and C8‐nitro substitution, and C4‐C4a olefination provided no increase in activity relative to 1, C8‐acetylamino substitution as in 5 and 8 was favourable. Moreover, to predict how the thieno[3,2‐h]cinnolinone inhibitors might bind to MMP‐8, the unsubstituted compound 9 was docked into the MMP‐8 crystal structure. These studies revealed that inhibitor 9 does not seem to be able to coordinate the catalytically‐active zinc ion but preferably interact with the peptide‐binding region of the active site.

Synthesis and pharmacological evaluation of 4,4a-dihydro-5H-[1]benzopyrano[4,3-c]pyridazin-3(2H)-ones bioisosters of antihypertensive and antithrombotic benzo[h]cinnolinones

Abstract A series of 4,4a-dihydro-5H-[1]benzopyrano[4,3- c ]pyridazin-3-(2H)-ones ( 2a–h ), have been prepared and evaluated for their pharmacological profile as antihypertensive and antithrombotic agents. Compounds 2 were ineffective in lowering the blood pressure of spontaneously hypertensive rats (SHR), only 2c (R 1 = NHCOCH 3 ) showing a short lasting action ( 2c and 2b (R 1 = NH 2 ) were found to be very active as antithrombotic agents in mice, being more potent than acetylsalicylic acid (ASA) taken as reference drug. Moreover, many derivatives of this class protected rats from formation of ASA or phenylbutazone (PBZ) induced ulcers, the most active being 2f (R 2 = OCH 3 ) (ED 50 = 12.2 mg/kg and 25.4 mg/kg po in ASA and PBZ models, respectively).

Synthesis and D2-like binding affinity of 4,5-dihydro-1H-benzo[g]indole-3-carboxamide derivatives as conformationally restricted 5-phenyl-pyrrole-3-carboxamide analogs ☆

A series of 4,5-dihydro-1H-benzo[g]-indole-3-carboxamide derivatives 2a-g were synthesized as conformationally restricted analogs of the dopamine D2-like 5-phenylpyrrole-3-carboxamide ligands and evaluated for their affinity for the dopamine D2-like receptors. In this series, N3-[(1-ethyltetrahydro-1H-2-pyrrolyl)methyl]-4,5-dihydro-1H-benzo[ g]indole- 3-carboxamide (2a) showed the highest affinity for D2-like receptors (IC50 = 160 nM). Replacement of the N-(1-ethyl-2-pyrrolidinyl)methyl side chain with a 2-(N,N-diethylamino)ethyl or a 1-benzyl-4-piperidinyl group (2b, 2d) decreased affinity for the D2-like receptor. The other compounds tested were found to be devoid of D2-like binding affinity.

Multitarget‐Directed Tricyclic Pyridazinones as G Protein‐Coupled Receptor Ligands and Cholinesterase Inhibitors

By following a multitarget ligand design approach, a library of 47 compounds was prepared, and they were tested as binders of selected G protein‐coupled receptors (GPCRs) and inhibitors of acetyl and/or butyryl cholinesterase. The newly designed ligands feature pyridazinone‐based tricyclic scaffolds connected through alkyl chains of variable length to proper amine moieties (e.g., substituted piperazines or piperidines) for GPCR and cholinesterase (ChE) molecular recognition. The compounds were tested at three different GPCRs, namely serotoninergic 5‐HT1A, adrenergic α1A, and dopaminergic D2 receptors. Our main goal was the discovery of compounds that exhibit, in addition to ChE inhibition, antagonist activity at 5‐HT1A because of its involvement in neuronal deficits typical of Alzheimer’s and other neurodegenerative diseases. Ligands with nanomolar affinity for the tested GPCRs were discovered, but most of them behaved as dual antagonists of α1A and 5‐HT1A receptors. Nevertheless, several compounds displaying this GPCR affinity profile also showed moderate to good inhibition of AChE and BChE, thus deserving further investigations to exploit the therapeutic potential of such unusual biological profiles.

Synthesis and pharmacological activity of 4-carbamoyl-5-aryl-6-methyl-4,5-dihydropyridazin-3 (2H)-ones

A new series of 4-carbamoyl-5-aryl-6-methyl-4,5-dihydropyridazin-3(2H)-ones have been synthesized and tested for their antiinflammatory and analgesic properties. Amongst the test compounds, only 31 showed antiinflammatory activity, though of shorter duration than that of indomethacin, taken as reference drug. On the contrary, many derivatives displayed relevant analgesic activity, 4--the only 4,5-dehydroderivative--being the most potent in the writhing test. In the hot plate test 3b, 3f and 3k were found to possess the most significant analgesic properties.

Tricyclic 3-(2H)-pyridazinone derivatives. Synthesis and evaluation of their antisecretory and antiulcer activity

Abstract A new series of benzopyranopyridazinones ( 1b–e ) either unsubstituted at the amide nitrogen or substituted by an alkyl thiourea, as well as two benzocinnolinone derivatives ( 2b, f ) have been synthesized and tested for their antiulcer and antisecretory activity. All the test compounds showed statistically significant antiulcer properties in the EtOH model, 1b being the most active. On the contrary, in the ASA model only 1b and 1d were found weakly active. In the pylorus-ligated rat model, 1b and 1e displayed significant antisecretory activity, though only 1b proved to be able to reduce the acidity of the gastric secretion.