Synthesis of Heteroaryl ortho-Phenoxyethylamines via Suzuki Cross-Coupling: Easy Access to New Potential Scaffolds in Medicinal Chemistry

Heteroaryl ortho-phenoxyethyl amines have been extensively employed in medicinal chemistry as privileged scaffolds for the design of highly potent and selective ligands. Herein we report an efficient, fast and general method for the synthesis of heteroaryl phenoxyethyl amines via Suzuki cross-coupling. This approach offers the opportunity to obtain a large variety of biaryls incorporating five-membered (thiophene, furan, thiazole, pyrazole, imidazole) or six-membered (pyridine, pyrimidine) heteroaromatic rings for appropriate libraries of ligands. All the compounds presented here have never been synthesized before and a full structural characterization is given

A New and Versatile Synthesis of 1,3-Dioxan-5-yl-pyrimidine and Purine Nucleoside Analogues

1,3-Dioxan-5-yl pyrimidine and purine nucleoside analogues were prepared following a new and versatile synthetic strategy. These analogues were synthesized via nucleophilic addition of the selected nucleobase to a 1,3-dioxane scaffold that presents an appropriate leaving group in position 5. In particular cis and trans isomers of purine/pyrimidine nucleosides and their halogenated homologues were obtained. NMR experiments, carried out on the cis isomers, led to assignment of an equatorial orientation to the 2-hydroxymethyl group and axial orientation to the nucleobase in position 5 of the 1,3-dioxane. The trans isomers showed a diequatorial orientation of these groups. These assignments were confirmed by X-ray crystallographic studie

1,3-Diossolani e analoghi aperti come nuovi ligandi per il recettore Sigma

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Investigation within a new series of heterocyclic biaryl piperazines acting at 5-HT1A serotoninergic receptors

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Synthesis and pharmacological evaluation of 1-benzylpiperazine and 4-benzylpiperidine as potent sigma ligands.

It is now well established that sigma receptors are an independent class of receptors expressed in peripheral organs and in the central nervous system. There are at least two identified subtypes, namely sigma1 and sigma2, with distinct functional roles and different pharmacological characteristics. On the basis of their neuroregulative and neuropotective functions sigma1 agents could be potentially used for the treatment of depression and psychiatric disorders. The finding of high concentration of sigma2 receptors in neuronal and non-neuronal tumor cell lines provides evidence of a possible role in anticancer therapy. A variety of chemically unrelated compounds is able to bind sigma receptors, however only few bind with high affinity and selectivity to sigma receptor subtypes. This situation has given new impulse to medicinal chemists for the search of new and more selective ligands.We have recently reported that substituted 1-benzylpiperazine and 4-benzylpiperidine derivatives were shown to be high-affinity sigma ligands (Ki in the nanomolar range) with a slight preference for sigma1 over sigma2 receptors1-2. With the aim to improve sigma1/sigma2 selectivity we have studied the effect of some substitutions of the oxygen atoms on the 1,3-dioxolane ring by synthesizing 1,3-oxathiolane, 1,3-dithiolane, tetrahydro-furan, cyclopentanone and cyclopentanol derivatives as depicted below. A spiro derivative was additionally prepared and tested to study the influence of the two aromatic rings on receptor affinity. The preliminary pharmacological results show a significant improvement of sigma1 selectivity for compound A. Structure-activity relationship will be extensively discussed during the congress

Derivati 1,3-diossanici come ligandi alpha1 adrenergici e 5-HT1A serotoninergici.

I recettori adrenergici alpha1 rappresentano una popolazione eterogenea e, dei tre sottotipi recettoriali farmacologicamente caratterizzati, il recettore α1A ha ricevuto la maggiore attenzione quale potenziale target per il trattamento dell’ipertrofia prostatica benigna (BPH). Mentre un numero consistente di antagonisti α1A sono attualmente disponibili, ligandi per i sottotipi α1B e α1D sono in numero limitato e posseggono uno scarso grado di selettività. Anche i recettori per la serotonina (5-HT) costituiscono una popolazione eterogenea e mostrano un elevato grado di omologia strutturale con i recettori alpha1 adrenergici. Questa e’ una delle ragioni che rende tuttora difficile la realizzazione di ligandi selettivi. Recentemente il nostro gruppo di ricerca ha individuato una nuova classe di antagonisti alpha1 adrenergici a struttura 1,3-diossolanica di cui i composti 1 e 2 rappresentano i termini più significativi della serie1. Studi di binding hanno dimostrato che questi composti si legano anche ai recettori 5-HT1A (1: Ki= 0.6 nM; 2: Ki=3.5 nM). In questo studio sono presentate le variazioni strutturali apportate ai composti lead 1 e 2 allo scopo di ottimizzare attività e selettività mediante:-omologazione dell’anello 1,3-diossolanico ad anello 1,3-diossanico -successiva variazione della distanza tra l’atomo di azoto e la porzione 2,2 difenilica, così come riportato nello schema seguente. I risultati farmacologici preliminari indicano che i nuovi composti si legano con buone affinità ai due sistemi recettoriali e che opportune modifiche strutturali indirizzano la selettività verso il recettore 5-HT1A, con una elevata attività di agonismo parziale

(2,2-difenil-[1,3]-diossolan-4ilmetil)-(3-fenil-propil)-ammina: nuovo agonista parziale del recettore serotoninergico 5-HT1A

ABSTRACT FA-CP-027

Ring opening effect at alpha1-adrenoceptor subtypes and 5-HT1A receptors within a novel class of 1,3-Dioxolane-based ligands

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Relazioni struttura-attività in una nuova serie di ligandi alpha1-adrenergici e 5-HT1A serotoninergici a struttura 2,2-difenil-[1,3]diossolanica

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