Modular Synthetic Platform for the Elaboration of Fragments in Three Dimensions for Fragment-Based Drug Discovery.

Fragment-based drug discovery (FBDD) is a key strategy employed in the hit-to-lead phase of pharmaceutical development. The rate-limiting step of this process is often identifying and optimizing synthetic chemistry suitable for fragment elaboration, especially in three dimensions (3-D). To address this limitation, we herein present a modular platform for the systematic and programmable elaboration of two-dimensional (2-D) fragment hits into lead-like 3-D compounds, utilizing nine bifunctional building blocks that explore a range of vectors in 3-D.

A Photoactivatable Version of Ivabradine Enables Light-Induced Block of HCN Current .

Therapeutic drugs, whose bioactivity is hindered by a photoremovable cage, offer the advantage of spatiotemporal confinement of their action to the target diseased tissue with improved bioavailability and efficacy. Here, we have applied such an approach to ivabradine (IVA), a bradycardic agent indicated for angina pectoris and heart failure, acting as a specific HCN channel blocker. To overcome the side effects due to its poor discrimination among HCN channel subtypes (HCN1-4), we prepared a caged version of IVA linked to a photocleavable bromoquinolinylmethyl group (BHQ-IVA).

Subnanomolar Affinity and Selective Antagonism at α7 Nicotinic Receptor by Combined Modifications of 2-Triethylammonium Ethyl Ether of 4-Stilbenol (MG624).

Modifications of the cationic head and the ethylene linker of 2-(triethylammonium)ethyl ether of 4-stilbenol (MG624) have been proved to produce selective α9*-nAChR antagonism devoid of any effect on the α7-subtype. Here, single structural changes at the styryl portion of MG624 lead to prevailing α7-nAChR antagonism without abolishing α9*-nAChR antagonism. Nevertheless, rigidification of the styryl into an aromatic bicycle, better if including a H-bond donor NH, such as 5-indolyl (), resulted in higher and more selective α7-nAChR affinity.

From 2-Triethylammonium Ethyl Ether of 4-Stilbenol (MG624) to Selective Small-Molecule Antagonists of Human α9α10 Nicotinic Receptor by Modifications at the Ammonium Ethyl Residue.

Nicotinic acetylcholine receptors containing α9 subunits (α9*-nAChRs) are potential druggable targets arousing great interest for pain treatment alternative to opioids. Nonpeptidic small molecules selectively acting as α9*-nAChRs antagonists still remain an unattained goal. Here, through modifications of the cationic head and the ethylene linker, we have converted the 2-triethylammonium ethyl ether of 4-stilbenol (MG624), a well-known α7- and α9*-nAChRs antagonist, into some selective antagonists of human α9*-nAChR.

Pyrrolidinyl benzofurans and benzodioxanes: Selective α4β2 nicotinic acetylcholine receptor ligands with different activity profiles at the two receptor stoichiometries.

A series of racemic benzofurans bearing N-methyl-2-pyrrolidinyl residue at C(2) or C(3) has been synthesized and tested for affinity at the α4β2 and α3β4 nicotine acetylcholine receptors (nAChRs). As previously reported for the benzodioxane based analogues, hydroxylation at proper position of benzene ring results in high α4β2 nAChR affinity and α4β2 vs. α3β4 nAChR selectivity.

Green Oxidation of Ketones to Lactones with Oxone in Water.

Cyclic ketones were quickly and quantitatively converted to 5-, 6-, and 7-membered lactones, very important synthons, by treatment with Oxone, a cheap, stable, and nonpollutant oxidizing reagent, in 1 M NaHPO/NaHPO water solution (pH 7). Under such simple and green conditions, no hydroxyacid was formed, thus making the adoption of more complex and non-eco-friendly procedures previously developed to avoid lactone hydrolysis unnecessary. With some changes, the method was successfully applied also to water-insoluble ketones such as adamantanone, acetophenone, 2-indanone, and the challenging cycloheptanone.

Determinants for α4β2 vs. α3β4 Subtype Selectivity of Pyrrolidine-Based nAChRs Ligands: A Computational Perspective with Focus on Recent cryo-EM Receptor Structures.

The selectivity of α4β2 nAChR agonists over the α3β4 nicotinic receptor subtype, predominant in ganglia, primarily conditions their therapeutic range and it is still a complex and challenging issue for medicinal chemists and pharmacologists. Here, we investigate the determinants for such subtype selectivity in a series of more than forty α4β2 ligands we have previously reported, docking them into the structures of the two human subtypes, recently determined by cryo-electron microscopy. They are all pyrrolidine based analogues of the well-known α4β2 agonist -methylprolinol pyridyl ether A-84543 and differ in the flexibility and pattern substitution of their aromatic portion.

Efficient conversion of d-mannitol into 1,2:5,6-diacetonide with Aquivion-H as a recyclable catalyst.

Heterogeneous solid catalysis by the commercially available perfluorosulfonic ionomer Aquivion-H allowed 1,2:5,6-diacetonide of d-mannitol (1), immediate precursor of important unichiral C3-synthons, to be efficiently obtained from d-mannitol and 2,2-dimethoxypropane in DMF at room temperature. The 1,2-monoacetonide, whose intermediate formation is the rate-limiting step, could be almost completely converted into 1 with limited concurrent transformation of 1 into triacetonides. In line with recent literature reports, these results indicate that heterogeneous catalysis by Aquivion-H surpasses the performances of homogeneous acidic catalysis assuring, presumably for its peculiar morphology, a higher product selectivity.

Modifications at C(5) of 2-(2-Pyrrolidinyl)-Substituted 1,4-Benzodioxane Elicit Potent α4β2 Nicotinic Acetylcholine Receptor Partial Agonism with High Selectivity over the α3β4 Subtype.

A series of diastereomeric 2-(2-pyrrolidinyl)-1,4-benzodioxanes bearing a small, hydrogen-bonding substituent at the 7-, 6-, or 5-position of benzodioxane have been studied for α4β2 and α3β4 nicotinic acetylcholine receptor affinity and activity. Analogous to C(5)H replacement with N and to a much greater extent than decoration at C(7), substitution at benzodioxane C(5) confers very high α4β2/α3β4 selectivity to the α4β2 partial agonism. Docking into the two receptor structures recently determined by cryo-electron microscopy and site-directed mutagenesis at the minus β2 side converge in indicating that the limited accommodation capacity of the β2 pocket, compared to that of the β4 pocket, makes substitution at C(5) rather than at more projecting C(7) position determinant for this pursued subtype selectivity.

1,4-Benzodioxane, an evergreen, versatile scaffold in medicinal chemistry: A review of its recent applications in drug design.

1,4-Benzodioxane has long been a versatile template widely employed to design molecules endowed with diverse bioactivities. Its use spans the last decades of medicinal chemistry until today concerning many strategies of drug discovery, not excluding the most advanced ones. Here, more than fifty benzodioxane-related lead compounds, selected from recent literature, are presented showing the different approaches with which they have been developed.

Behavioural and pharmacological profiles of zebrafish administrated pyrrolidinyl benzodioxanes and prolinol aryl ethers with high affinity for heteromeric nicotinic acetylcholine receptors.

Rationale: Prolinol aryl ethers and their rigidified analogues pyrrolidinyl benzodioxanes have a high affinity for mammalian α4β2 nicotinic acetylcholine receptors (nAChRs). Electrophysiological studies have shown that the former are full agonists and the latter partial agonists or antagonists of human α4β2 receptors, but their in vivo effects are unknown.

Objectives And Methods: As α4β2 nAChRs play an important role in the cognition and the rewarding effects of nicotine, we tested the effects of two full agonists and one antagonist on spatial learning, memory and attention in zebrafish using a T-maze task and virtual object recognition test (VORT).