Christian F. Masaguer

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.

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.

Integrated Ugi-based assembly of functionally, skeletally, and stereochemically diverse 1,4-benzodiazepin-2-ones.

A practical, integrated and versatile U-4CR-based assembly of 1,4-benzodiazepin-2-ones exhibiting functionally, skeletally, and stereochemically diverse substitution patterns is described. By virtue of its convergence, atom economy, and bond-forming efficiency, the methodology documented herein exemplifies the reconciliation of structural complexity and experimental simplicity in the context of medicinal chemistry projects.

Efficient synthesis of quinazolinones as intermediates of CNS agents via inverse-electron demand Diels–Alder reaction☆

Abstract Enaminones undergo inverse electron demand Diels–Alder reaction with 1,3,5-triazine, allowing access to functionalised quinazolinones as intermediates in the synthesis of CNS agents. This reaction is highly dependent of the solvent: 1,3,5-triazine undergoes single or double [4+2] cycloadditions with enaminones, and quinazolinones or acridinediones can be selectively obtained.

A practical and efficient route for synthesis of 6-aminomethyl-4-oxo-4,5,6,7-tetrahydroindoles as new CNS agent precursors

Abstract Starting from 2,5-dimethoxybenzoic acid we described a practical and efficient route for synthesis of 6-aminomethyl-4-oxotetrahydroindoles with good to acceptable overall yields of 50-30%.

Butyrophenone analogues in the carbazole series as potential atypical antipsychotics: synthesis and determination of affinities at D2, 5-HT2A, 5-HT2B and 5-HT2C receptors#

We describe practical and efficient routes for synthesis of 2-aminomethyl-1,2,3,9-tetrahydro-4H-carbazol-4-ones using the Fischer indole synthesis or palladium-catalysed cyclization methodologies, as well as their affinities for D(2), 5-HT(2A) and 5-HT(2C) receptors, and their activity at the 5-HT(2B) receptor. The most active compounds, 4b (QF 2003B) and 4c (QF 2004B), with a pK(i) (5-HT(2A)/D(2)) ratio of 1.28 show a potential antipsychotic profile according to Meltzers classification.

Synthesis, 3D-QSAR, and Structural Modeling of Benzolactam Derivatives with Binding Affinity for the D2 and D3 Receptors

A series of 37 benzolactam derivatives were synthesized, and their respective affinities for the dopamine D2 and D3 receptors evaluated. The relationships between structures and binding affinities were investigated using both ligand‐based (3D‐QSAR) and receptor‐based methods. The results revealed the importance of diverse structural features in explaining the differences in the observed affinities, such as the location of the benzolactam carbonyl oxygen, or the overall length of the compounds. The optimal values for such ligand properties are slightly different for the D2 and D3 receptors, even though the binding sites present a very high degree of homology. We explain these differences by the presence of a hydrogen bond network in the D2 receptor which is absent in the D3 receptor and limits the dimensions of the binding pocket, causing residues in helix 7 to become less accessible. The implications of these results for the design of more potent and selective benzolactam derivatives are presented and discussed.

Preparation of (R)-(−)- and (S)-(+)-3-hydroxymethyl-1-tetralone tosylates, key intermediates in the synthesis of new CNS drugs, via resolution of precursors

Abstract The preparation of ( R )-(−)- and ( S )-(+)-3-hydroxymethyl-1-tetralone tosylates, key intermediates in the synthesis of new CNS drugs in the aminobutyrophenone family, has been developed via classical resolutions or lipase-catalyzed kinetic resolution of one of their precursors.

New synthetic approaches to CNS drugs. A straightforward, efficient synthesis of tetrahydroindol-4-ones and tetrahydroquinolin-5-ones via palladium-catalyzed oxidation of hydroxyenaminones

We have developed a facile and efficient synthesis of new conformationally restricted butyrophenones in the indole and quinoline series via palladium-catalyzed oxidation of hydroxyenaminones, and subsequent cyclization followed by spontaneous aromatization.