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

Effect of the replacement of the o-methoxyphenyl moiety with nitrogen-containing aromatic rings within N-phenyl-piperazine and phenoxy-ethylamine-based 1,3-dioxo/oxathio/dithiolanes as α1 and 5-HT1A receptor ligands

In the present work, nineteen analogues of 1-[(2,2-Diphenyl-1,3-dioxolan-4-yl)methyl]-4-(2-methoxyphenyl)piperazine 5 and N-[2-(2-Methoxyphenoxy)ethyl]-2,2-diphenyl-1,3-dioxolane-4-methanamine 18 were synthesized. The compounds were tested for binding affinity at 5-HT1AR and α1-AR subtypes. They were also tested using functional assays as α1-AR antagonists and the most promising were tested for functional activity at 5-HT1AR, where they were shown to behave as agonists. The results highlight that the replacement of the 1,3-dioxolane ring with a 1,3-oxathiolane or a 1,3-dithiolane moiety leads to an overall reduction in in-vitro affinity at the α1-AR, while affinity, potency and efficacy were strongly enhanced at the 5-HT1A receptor. Overall, the nitrogen-containing aromatic moieties scarcely affect the affinity at the 5-HT1A receptor, while reducing potency and increasing efficacy. The oxidation of the sulphur atom in the 1,3-oxathiolane to give sulfoxides and solfones has a negative effect on affinity and potency at both receptor systems. Regardless of the effect on the other parameters, selectivity toward 5-HT1AR with respect to the α1-AR is often favoured, but never the contrary. The most striking result is the inversion of selectivity. In fact, while the lead 5 is 100-fold selective for α1-AR, the new derivatives, although to differing degrees, are selective for 5-HT1AR

Constrained 1,4-dialkylpiperazines as monoamine transporters inhibitors for cocaine-related abuse

Cocaine abuse and addiction remain grave health and societal problems with nearly 11,000 overdose deaths in 2015. Despite the high prevalence of cocaine use, no FDA-approved therapeutic for treating cocaine addiction has been achieved. The primary target for cocaine is dopamine transporter (DAT) and the rewarding and reinforcing effects of cocaine are mediated predominantly by its inhibition, with a consequent ‘reverse agonist’ effect. Several DAT inhibitors have been proposed as potential drugs for cocaine abuse.[1-2] One of the most studied DAT inhibitors, GBR12909 (Ki DAT = 3.7 nM), is able to slightly increase DA level and to blunt the cocaine-induced elevation of extracellular DA in vivo without exerting the central exciting effects of cocaine and addiction. Unfortunately, the phase I clinical trials failed, due to its cardiotoxicity.[3-4] In a lead optimisation program focused to identify novel and safe GBR12909 analogues, nine constrained derivatives were design and synthesized in a ligand based approach. Maintaining unaltered the fluoro-phenyl and phenylpropylpiperazine moiety, the rigidification of the ethylene ether, by means of tetrahydrofuran, dioxolane, dioxane, oxathiolane and dithiolane ring, was investigated in a focused SAR study (Fig. 1). All the compounds were assayed for the determination of the binding affinity for DAT, NET and SERT. In particular, two dioxolane derivatives displayed a binding affinity comparable to that of GBR12909, with Ki of 21.2 and 13.9 nM for DAT, and a selectivity ratio SERT/DAT > 30. Since the cyclization introduces one chiral centre, the two enantiomers of one racemic mixture were prepared following enantioselective synthetic procedures. The (R)- and (S)-forms showed a binding affinity comparable to the one determined for the racemate (Ki DAT of 16 and 46 nM, respectively), suggesting that the configuration of the stereocenters slightly affect the binding to the DAT transporter. For the most interesting derivatives, uptake inhibition assays were conducted in rat brain synaptosomes. It was observed that the potency trend parallel the affinity values

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

Enigmatic Receptors

The identification of new binding sites raises the problem of defining their role, if any. At times they are shown to be pharmacological receptors, in a strict sense, as they fulfill certain requirements, and a precise physiological role and function, and an endogenous ligand (neurotransmitter) are discovered. At other times, however, neither a clear physiological role nor an endogenous ligand are found, but the term “receptor” is still used, although it may not be a proper one in the conventional pharmacological sense. Furthermore, no clear intracellular signalling transduction pathway is defined and, as a consequence, it is not possible to determine whether drugs binding to these receptors act as agonists or antagonists. What their structure and biological function are and how they mediate the pharmacological effects of ligands may remain for a long time an enigma. The matter, in any case, is of great interest to researchers of different areas, especially to medicinal chemists who foresee novel potential targets for therapeutic interventions. In this meeting one section is dedicated to two examples of this kind of receptors: imidazoline (I) and sigma (σ) receptors

MOLECULAR REQUIREMENTS OF THE ACTIVE SITESOF THE CHOLINERGIC RECEPTORSXVI (x) - Synthesis qnd cholinergic activity ol 2- or 5-alkyl or 5-phenyl--4-methyl-3-oxo-1 -dimethylaminomethylcy clopentane methiodide.

In order to study the cholinergic receptor through affinitychromatography, some derivatives ol deoxamuscarone (1 a) incorporating alkyl and phenyl substituents at the positions 2 and 5 were synthesizedas model compounds. However, the sharp drop in activity and the lack of discrimination between nicotinic and muicarinic receptors exhibited by thecompounds discourage their further development as affinity reagent

Recettori e farmaci

A partire dalla seconda met\ue0 del secolo scorso i chimici farmaceutici di tutto il mondo sono stati impegnati assiduamente, spesso con successo ma ancora pi\uf9 spesso con risultati limitati, a progettare e sintetizzare molecole attive su diversi target recettoriali. Si cita a titolo di esempio l\u2019enorme quantit\ue0 di ligandi realizzati con lo scopo di caratterizzare il sito di riconoscimento dei diversi sottotipi recettoriali muscarinici, che ha fornito, in particolare per la classe degli agonisti, risultati per la maggior parte deludenti.Le ragioni di questo parziale fallimento sono apparse chiare solo successivamente, cio\ue8 con la scoperta della sostanziale identit\ue0 in termini di sequenza aminoacidica del sito di riconoscimento nei vari sottotipi. Nonostante queste difficolt\ue0, tale approccio ha permesso la scoperta di un gran numero di molecole che hanno un recettore come target e che sono state introdotte in terapia come farmaci. Negli ultimi anni la risoluzione cristallografica dei recettori di membrana ha decisamente accelerato l\u2019acquisizione di conoscenze, facendo prospettare tempi molto pi\uf9 brevi per la progettazione di nuovi ligandi. \uc8 doveroso ricordare che nel nostro Paese la ricerca sui recettori \ue8 stata continua e di grande rilievo: dedicare ai recettori un capitolo di questo libro rende merito ai chimici farmaceutici e alle loro scoperte, che costituiscono un tassello importante nella comprensione della struttura e funzionalit\ue0 recettoriale

SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF CYCLIC AND OPENED THIOANALOGUES OF PIPEROXAN

Three piperoxan analogues, derived from the opening of the benzodioxane ring and/or replacement of the oxygen atom with the less polar sulfur, were synthesized. The decrease of the -blocking activity found for these compounds showed that the binding site of benzodioxane-like compounds does not accept the substitution with less polar groups

Pyrrolidine Derivatives as New Ligands for 5-HT1A Receptors

Our research group has long been involved in the development of new 5-HT1A selective ligands and 1,3-dioxolane derivatives bearing a phenoxyethylamine basic portion in position 4 were reported1. They were shown to have interesting 5-HT1A agonist activity accompanied by a good affinity, even if a certain alpha1 affinity was still present. 5-HT1A agonists and partial agonists have proved useful in the treatment of neuropsychiatric disorders such as anxiety and depression, to prevent neurodegeneration and for their antinociceptive activity2,3. On this basis and with the aim to improve 5-HT1A affinity and selectivity, compound A derivatives have been synthesized. A frozen structure of the ethylamine portion characterizes the new ligand and this variation4 with respect to the lead A has been designed in order to decrease the flexibility of this part of the molecule (figure 1). Stereospecific synthesis has been planned to give the desired four enantiomers (figure 1) so that it has been evaluated: 1. the effect on 5-HT1A affinity of the molecular rigidity provided by pyrrolidine core in comparison to that of the lead compound A; 2. stereoisomeric preferences for the receptor interaction. Several reactions and different synthetic schemes have been followed to obtained these four stereoisomers with good yield and a process optimization has been pursued. Structural characterization by NMR and mass (Q-TOF) analysis have been performed on the final compounds together with their optical purity determination

MOLECULAR. REQUIR.EMENTS OF THE ACTIVE SITESOF THE CHOLINERGIC RECEPTORS

Some cyclopentene derivatives lacking the oxygenatedlunctions have been sltnthesized and tested as cholinergic compounds. Theirgood muscarinic potency seems to confirm that such compounds interactwith a receptor area which is not coincident with that recognized by othercholinergic agents such as muscarine and deoxamuscarine