Synthesis and biological evaluation of a series of aminoalkyl-tetralones and tetralols as dual dopamine/serotonin ligands.

A series of novel α-tetralone and α-tetralol derivatives was synthesized, and their binding affinities for 5-HT(2A) and D2 receptors, the most important targets implicated in the anti-schizophrenia drug action, were evaluated to elucidate how substitutions in the aromatic ring of the pharmacophore affect to the affinity or selectivity for these receptors. The replacement of the H-7 in the tetrahydronaphthalene system by an amino group resulted in privileged 5-HT(2A) affinity of the 6-fluorobenzo[d]isoxazol derivative 36 and the alcohol 25 both showing a pK(i) value for 5-HT(2A) higher than 8.3 and good binding affinities for D2 receptor leading to a Meltzer's ratio characteristic of an atypical antipsychotic profile. Additionally, a small collection of 3-aminomethyltetralone derivatives was prepared and examined here for their affinities and selectivities as 5-HT(2A)/D2 dual ligands. Compound 11 shows the best profile with good pKi values for 5-HT(2A) and D2 receptors leading to a Meltzer's ratio characteristic of a typical antipsychotic behaviour. These three compounds behaved as competitive antagonists of both 5-HT(2A) and D2 receptors, and might be promising pharmacological tools for the investigation of the dual function of the 5HT(2A)-D2 ligands.

Synthesis and binding affinity of potential atypical antipsychotics with the tetrahydroquinazolinone motif.

A series of 8 new tetrahydroquinazolinone derivatives was synthesized and evaluated for binding affinity to D2 and 5-HT2A human receptors; in addition, some properties related to blood-brain barrier penetration were calculated. From the results of these assays, three compounds were selected for further binding tests on D1, D3, and 5-HT2C human receptors, which are thought to be involved in schizophrenia. From these data, compound 19b emerged as the most promising candidate based on its good binding affinities for D1, D2, and D3 receptors, high affinity for 5-HT2A, low affinity for 5-HT2C receptors, and a Meltzer's ratio characteristic of an atypical antipsychotic profile.

Synthesis, binding affinity and SAR of new benzolactam derivatives as dopamine D3 receptor ligands.

A series of new benzolactam derivatives was synthesized and the derivatives were evaluated for their affinities at the dopamine D(1), D(2), and D(3) receptors. Some of these compounds showed high D(2) and/or D(3) affinity and selectivity over the D(1) receptor. The SAR study of these compounds revealed structural characteristics that decisively influenced their D(2) and D(3) affinities. Structural models of the complexes between some of the most representative compounds of this series and the D(2) and D(3) receptors were obtained with the aim of rationalizing the observed experimental results. Moreover, selected compounds showed moderate binding affinity on 5-HT(2A) which could contribute to reducing the occurrence of extrapyramidal side effects as potential antipsychotics.

Synthesis, binding affinity, and molecular docking analysis of new benzofuranone derivatives as potential antipsychotics.

The complex etiology of schizophrenia has prompted researchers to develop clozapine-related multitarget strategies to combat its symptoms. Here we describe a series of new 6-aminomethylbenzofuranones in an effort to find new chemical structures with balanced affinities for 5-HT2 and dopamine receptors. Through biological and computational studies of 5-HT2A and D2 receptors, we identified the receptor serine residues S3.36 and S5.46 as the molecular keys to explaining the differences in affinity and selectivity between these new compounds for this group of receptors. Specifically, the ability of these compounds to establish one or two H-bonds with these key residues appears to explain their difference in affinity. In addition, we describe compound 2 (QF1004B) as a tool to elucidate the role of 5-HT2C receptors in mediating antipsychotic effects and metabolic adverse events. The compound 16a (QF1018B) showed moderate to high affinities for D2 and 5-HT2A receptors, and a 5-HT2A/D2 ratio was predictive of an atypical antipsychotic profile.

Synthesis, adenosine receptor binding and 3D-QSAR of 4-substituted 2-(2'-furyl)-1,2,4-triazolo[1,5-a]quinoxalines.

A collection of 25 2-(2'-furyl)-1,2,4-triazolo[1,5-a]quinoxalines incorporating different substitution patterns at position 4 have been synthesized and their binding affinity towards human adenosine receptors (hA(1), hA(2A), hA(2B) and hA(3)) was determined. The biological data show that several potent at hA(1), but lightly selective, adenosine ligands were identified. Moreover, these results confirmed the hypothesis that the structural modifications carried out on the 4-position of the tricyclic system produces a remarkable modification of the adenosine receptorial profile. A 3D-QSAR modelling study (GRIND/ALMOND methodology) performed on the hA(1) data gave further support to the pharmacological results, and it is presented as a useful tool for the future design of ligands with better pharmacological profiles.

1-, 3- and 8-substituted-9-deazaxanthines as potent and selective antagonists at the human A2B adenosine receptor.

A large series of piperazin-, piperidin- and tetrahydroisoquinolinamides of 4-(1,3-dialkyl-9-deazaxanthin-8-yl)phenoxyacetic acid were prepared through conventional or multiple parallel syntheses and evaluated for their binding affinity at the recombinant human adenosine receptors, chiefly at the hA(2B) and hA(2A) receptor subtypes. Several ligands endowed with high binding affinity at hA(2B) receptors, excellent selectivity over hA(2A) and hA(3) and a significant, but lower, selectivity over hA(1) were identified. Among them, piperazinamide derivatives 23 and 52, and piperidinamide derivative 69 proved highly potent at hA(2B) (K(i)=11, 2 and 5.5 nM, respectively) and selective towards hA(2A) (hA(2A)/hA(2B) SI=912, 159 and 630, respectively), hA(3) (hA(3)/hA(2B) SI=>100, 3090 and >180, respectively) and hA(1) (hA(1)/hA(2B) SI=>100, 44 and 120, respectively), SI being the selectivity index. A number of selected ligands tested in functional assays in vitro showed very interesting antagonist activities and efficacies at both A(2A) and A(2B) receptor subtypes, with pA(2) values close to the corresponding pK(i)s. Structure-affinity and structure-selectivity relationships suggested that the binding potency at the hA(2B) receptor may be increased by lipophilic substituents at the N4-position of piperazinamides and that an ortho-methoxy substituent at the 8-phenyl ring and alkyl groups at N1 larger than the ones at N3, in the 9-deazaxanthine ring, may strongly enhance the hA(2A)/hA(2B) SI.

Design, synthesis, and structure-activity relationships of a novel series of 5-alkylidenepyridazin-3(2H)-ones with a non-cAMP-based antiplatelet activity.

5-alkylidenepyridazin-3-ones with four points of diversity (R2, R6, X, Y) have been synthesized and evaluated as platelet aggregation inhibitors. Several derivatives eliciting antiplatelet activity in the low micromolar range (e.g., 14e, 14k, 14p, 14v, IC50 congruent with 1 microM) were identified. Structure-activity relationships studies on these compounds revealed the key molecular determinants of this new family of antiplatelet agents: (a) two ester groups in the alkoxy moieties; (b) lipophilic substituents at the N2 position of the pyridazin-3-one. The preliminary results of a pharmacological study aimed at determining the mechanism of action of a set of representative compounds revealed that, unlike other pyridazinones, the documented antiplatelet effect is not a consequence of a PDE-III inhibitory activity.

Synthesis and binding affinity of new pyrazole and isoxazole derivatives as potential atypical antipsychotics.

We describe the synthesis and binding affinities on D(2), 5-HT(2A) and 5-HT(2C) receptors of 6-aminomethyl-6,7-dihydro-1H-indazol-4(5H)-ones and 6-aminomethyl-6,7-dihydro-3-methyl-benzo[d]isoxazol-4(5H)-ones, as conformationally constrained butyrophenone analogues. One of the new compounds showed good in vitro binding features, and a Meltzer's ratio characteristic of an atypical antipsychotic profile.

Multistructure 3D-QSAR studies on a series of conformationally constrained butyrophenones docked into a new homology model of the 5-HT2A receptor.

The present study is part of a long-term research project aiming to gain insight into the mechanism of action of atypical antipsychotics. Here we describe a 3D-QSAR study carried out on a series of butyrophenones with affinity for the serotonin-2A receptor, aligned by docking into the binding site of a receptor model. The series studied has two peculiarities: (i) all the compounds have a chiral center and can be represented by two enantiomeric structures, and (ii) many of the structures can bind the receptor in two alternative orientations, posing the problem of how to select a single representative structure for every compound. We have used an original solution consisting of the simultaneous use of multiple structures, representing different configurations, binding conformations, and positions. The final model showed good statistical quality (n = 426, r2 = 0.84, q2LOO = 0.81) and its interpretation provided useful information, not obtainable from the simple inspection of the ligand-receptor complexes.

Synthesis and biological evaluation of new quinazoline and cinnoline derivatives as potential atypical antipsychotics.

Four new diaza analogues (14, 15, 23, and 24) of the conformationally constrained aminobutyrophenone derivatives QF0104B (5) and QF0108B (6) were synthesized (Schemes 2 and 3), and evaluated for their binding affinities (Table) towards the serotonin 5-HT2A and 5-HT2C, and the dopamine D2 receptors. Among the new compounds, the quinazoline derivative 15 (= 7-{[4-(4-fluorobenzoyl)piperidin-1-yl]methyl}-5,6,7,8-tetrahydroquinazolin-5-one) exhibited the highest affinities towards the serotonin 5-HT2A and dopamine D2 receptors, and it is in the borderline of potential atypical antipsychotics. The cinnoline derivative 23 (= 7-{[4-(4-fluorobenzoyl)piperidin-1-yl]methyl}-5,6,7,8-tetrahydro-3-methylcinnolin-5-one) displayed high selectivity in its binding profile towards the 5-HT2C compared to both the 5-HT2A and D2 receptors.

QF2004B, a potential antipsychotic butyrophenone derivative with similar pharmacological properties to clozapine.

The aim of the present work was to characterize a lead compound displaying relevant multi-target interactions, and with an in vivo behavioral profile predictive of atypical antipsychotic activity. Synthesis, molecular modeling and in vitro and in vivo pharmacological studies were carried out for 2-[4-(6-fluorobenzisoxazol-3-yl)piperidinyl]methyl-1,2,3,4-tetrahydro-carbazol-4-one (QF2004B), a conformationally constrained butyrophenone analogue. This compound showed a multi-receptor profile with affinities similar to those of clozapine for serotonin (5-HT2A, 5-HT1A, and 5-HT2C), dopamine (D1, D2, D3 and D4), alpha-adrenergic (alpha1, alpha2), muscarinic (M1, M2) and histamine H1 receptors. In addition, QF2004B mirrored the antipsychotic activity and atypical profile of clozapine in a broad battery of in vivo tests including locomotor activity (ED50 = 1.19 mg/kg), apomorphine-induced stereotypies (ED50 = 0.75 mg/kg), catalepsy (ED50 = 2.13 mg/kg), apomorphine- and DOI (2,5-dimethoxy-4-iodoamphetamine)-induced prepulse inhibition (PPI) tests. These results point to QF2004B as a new lead compound with a relevant multi-receptor interaction profile for the discovery and development of new antipsychotics.

Design, synthesis, and structure-activity relationships of 1-,3-,8-, and 9-substituted-9-deazaxanthines at the human A2B adenosine receptor.

Over two hundred 1-, 3-, 8-, and 9-substituted-9-deazaxanthines were prepared and evaluated for their binding affinity at the recombinant human adenosine receptors, in particular at the hA(2B) and hA(2A) subtypes. Several ligands endowed with sub-micromolar to low nanomolar binding affinity at hA(2B) receptors, good selectivity over hA(2A) and hA(3), but a relatively poor selectivity over hA(1) were obtained. Good antagonistic potencies and efficacies, with pA(2) values close to the corresponding pK(i)s, were observed in functional assays in vitro performed on a selected series of compounds. 1,3-Dimethyl-8-phenoxy-(N-p-halogenophenyl)-acetamido-9-deazaxanthine derivatives appeared as the most interesting leads, some of them showing outstanding hA(2B) affinities, high selectivity over hA(2A) and hA(3), but low selectivity over hA(1). Structure-affinity relationships suggested that the binding potency at the hA(2B) receptor was mainly modulated by the steric (lipophilic) properties of the substituents at positions 1 and 3 and by the electronic and lipophilic characteristics of the substituents at position 8. A comparison among affinity and selectivity profiles of 9-deazaxanthines with the corresponding xanthines suggested some possible differences in their binding mode.

Pyridazines part 41: synthesis, antiplatelet activity and SAR of 2,4,6-substituted 5-(3-oxo-3-phenylprop-1-en-1-yl)- or 5-(3-phenylprop-2-enoyl)pyridazin-3(2H)-ones.

As part of the optimization process of the lead compound I a focussed library of diversely substituted pyridazin-3(2H)-ones containing a 3-oxo-3-phenylprop-1-en-1-yl or 3-phenylprop-2-enoyl fragment at position 5 has been obtained and evaluated as antiplatelet agents. The structural modification at positions 2, 6 and 4 of the heterocyclic moiety allowed us to obtain preliminary information on the structure-activity relationship in this family.

Synthesis and binding affinity of novel 3-aminoethyl-1-tetralones, potential atypical antipsychotics.

A series of 3-aminoethyl-1-tetralones, conformationally constrained higher homologues of haloperidol (standard for typical antipsychotic profile), have been obtained by a four-step route from valerolactone. Their binding affinities at dopamine D(2) and serotonin 5-HT2A and 5-HT2C receptors were determined, showing in some cases an atypical antipsychotic profile.

8-Substituted-9-deazaxanthines as adenosine receptor ligands: design, synthesis and structure-affinity relationships at A2B.

A number of 8-substituted-9-deazaxanthine derivatives (1,3-dialkyl-6-substituted-1H-pyrrolo[3,2-d]pyrimidine-2,4(3H,5H)-diones) were prepared and tested for their antagonistic activity at the recombinant human adenosine receptors, in particular at the A(2B) and A(2A) receptor subtypes. Compounds endowed with micromolar to nanomolar binding affinities, but with poor A(2B)/A(2A) selectivity, were obtained. Preliminary quantitative structure-affinity relationships suggested that the binding potency at the A(2B) receptor is mainly modulated by the electronic and lipophilic properties of the ligands.

Chemoenzymatic synthesis and binding affinity of novel (R)- and (S)-3-aminomethyl-1-tetralones, potential atypical antipsychotics.

A series of (R)- and (S)-3-aminomethyl-1-tetralones, conformationally constrained analogues of haloperidol, have been obtained by enzymatic resolution of the corresponding racemic 3-hydroxymethyl-1-tetralones using Pseudomonas fluorescens lipase. Their binding affinities at dopamine D(2) and serotonin 5-HT(2A) and 5-HT(2C) receptors were determined showing in some cases an atypical antipsychotic profile with Meltzer's ratio higher than 1.30.

Pyridazines. Part 36: Synthesis and antiplatelet activity of 5-substituted-6-phenyl-3(2H)-pyridazinones.

A convenient and efficient palladium-catalysed retro-ene-assisted method has been developed to prepare a series of 5-substituted-6-phenyl-3(2H)-pyridazinones as potential antiplatelet drugs. The most active compounds were those that contain a 3-phenyl-3-oxo-propenyl fragment or a phenylthio group at position 5 of the heterocyclic ring.

Synthesis of 1-substituted-6-methyluracils.

A series of 6-methyl-1H-pyrimidin-2,4-diones bearing different substituents in the 1-position of the uracil ring were prepared starting from substituted ureas and diketene.

Conformationally constrained butyrophenones as new pharmacological tools to study 5-HT 2A and 5-HT 2C receptor behaviours.

This study presents new pharmacological and molecular modelling studies on a recently described series of conformationally constrained butyrophenones. Alignment-free three-dimensional quantitative structure-activity relationship models developed on the basis of GRid Independent descriptors and partial least squares regression analysis, allow feasible predictions of activity of new compounds and reveal structural requirements for optimal affinity, particularly in the case of the 5-HT(2A) receptor. The requirements for the 5-HT(2A) affinity consist in a precise distance between hydrogen bond donor (protonated amino group) and hydrogen bond acceptor groups, as well as an optimal distance between the protonated amino group and the farthest extreme of the compounds. Another significant result has been the characterisation of two structurally similar compounds as interesting pharmacological tools (1-[(4-Oxo-4,5,6,7-tetrahydrobenzo[b]furan-5-yl)ethyl]-4-(6-fluorobenzisoxazol-3-yl)piperidine and 1-[(4-Oxo-4,5,6,7-tetrahydrobenzo[b]furan-6-yl)methyl]-4-(6-fluorobenzisoxazol-3-yl)piperidine). In spite of their structural similarity, the first compound shows clearly higher affinity for the 5-HT(2C) receptor (about 100 fold) and higher Meltzer ratio (1.17 vs. 0.99) than the second. Moreover, the first compound inhibits arachidonic acid release in a biphasic concentration-dependent way in functional experiments at the 5-HT(2A) receptor and it acts as inverse agonist at the 5-HT(2C) receptor, behaviours that are not shown by the second compound.

Pyridazine derivatives 32: Stille-based approaches in the synthesis of 5-substituted-6-phenyl-3(2H)-pyridazinones.

A series of 6-phenyl-3(2H)-pyridazinones bearing different substituents in the 5-position of the pyridazinone ring were prepared using Stille-based approaches in the search for new platelet-aggregation inhibitors.