2-{-[ω-(1-Benzylpiperidin-4-yl)alkyl]amino}-6-[(prop-2-yn-1-yl)amino]pyridine-3,5-dicarbonitriles Showing High Affinity for σ Receptors.

Sigma receptors (σRs) represent very attractive biological targets for the development of potential agents for the treatment of several neurological disorders. In the search for new small molecule drugs against neuropathic pain, we identified 2-{[2-(1-benzylpiperidin-4-yl)ethyl]amino}-6-[methyl(prop-2-yn-1-yl)amino]pyridine-3,5-dicarbonitrile () as a polyfunctionalized small pyridine with potent dual-target activities against acetylcholinesterase (AChE) (IC = 13 nM) and butyrylcholinesterase (BuChE) (IC = 3.1 µM), exhibiting high σR affinity ((hσR) = 1.

Stereoselective Synthesis and Biological Evaluation of Perhydroquinoxaline-Based κ Receptor Agonists.

The hydroxylated perhydroquinoxaline was designed by conformational restriction of the prototypical κ receptor agonist U-50,488 and the introduction of an additional polar group. The synthesis of comprised ten reaction steps starting from diethyl 3-hydroxyglutarate (). The first key step was the diastereoselective establishment of the tetrasubstituted cyclohexane by the reaction of dialdehyde with benzylamine and nitromethane.

Synthesis and structure-affinity relationships of spirocyclic σ receptor ligands with tetrahydropyran scaffold.

The σ receptor plays a key role in the regulation of various processes in the human body; it is involved in the development of neurodegenerative and neuropsychiatric diseases and is overexpressed in several human tumors rendering it an important target for potential drug candidates. In this project, spirocyclic σ receptor ligands with different substituents in 4- and 9-position were synthesized and investigated for their σ receptor affinity and selectivity over related targets. The σ affinity of the ligands was correlated with their lipophilicity (logD value) giving insight into their lipophilic ligand efficiency (LLE).

Enantiomerically Pure Indazole Bioisosteres of Ifenprodil and Ro 25-6981 as Negative Allosteric Modulators of NMDA Receptors with the GluN2B Subunit.

Administration of negative allosteric modulators of GluN2B subunit-containing NMDA receptors such as Ro 25-6981 () and ifenprodil () results in neuroprotective effects. In this study, the phenol of and was replaced bioisosterically by an indazole to inhibit glucuronidation. The γ- and β-aminoalcohols and were prepared without installing a protective group at the indazole ring using the ketone as a common intermediate.

Two-Step Synthesis of Enantiomerically Pure Morphans from (R)-Carvone.

Enantiomerically pure 4-hydroxymorphan-7-ones were prepared in two steps from the natural product (R)-carvone. At first, the isopropenyl moiety of (R)-carvone was converted into the epoxide 7. A Domino reaction consisting of epoxide opening with primary amines followed by intramolecular conjugate addition of the resulting secondary amines at the α,β-unsaturated ketone established the morphan scaffold.

Quinolone bioisosteres of phenolic GluN2B-selective NMDA receptor antagonists.

Cyclopenta[g]quinolones of type 4 were designed with the aim to bioisosterically replace the phenol of potent GluN2B ligands such as ifenprodil and Ro 25-6981 by the quinolone system and to restrict the conformational flexibility of the aminopropanol substructure in a cyclopentane system. The designed ligands were synthesized in an eight-step sequence starting with terephthalaldehyde (5). Key steps pf the synthesis were the intramolecular Friedel-Crafts acylation of propionic acids 10 to yield the cyclopenta[g]quinolinediones 11 and the Mannich reaction of diketone 11a followed by conjugate addition at the α,β-unsaturated ketone 12a.

Sigma receptor and aquaporin modulators: chiral resolution, configurational assignment, and preliminary biological profile of RC752 enantiomers.

The key role of chiral small molecules in drug discovery programs has been deeply investigated throughout last decades. In this context, our previous studies highlighted the influence of the absolute configuration of different stereocenters on the pharmacokinetic, pharmacodynamic and functional properties of promising Sigma receptor (SR) modulators. Thus, starting from the racemic SR ligand RC752, we report herein the isolation of the enantiomers via enantioselective separation with both HPLC and SFC.

Diastereoselective synthesis and structure-affinity relationships of receptor ligands with spirocyclic scaffold.

Spirocyclic scaffolds play an increasing role in drug discovery as they define a rigid three-dimensional space to increase specific interactions with protein binding sites. Herein, a spirocyclic center was introduced into the lead compound 1 to rigidify its flexible benzylaminoethyl side chain. The key step of the synthesis was the reaction of different α,β-unsaturated amides 6 and 13-16 with methyl acrylate in the presence of TBDMSOTf.

Negative allosteric modulators of NMDA receptors with GluN2B subunit: synthesis of β-aminoalcohols by epoxide opening and subsequent rearrangement.

In order to obtain novel antagonists of GluN2B subunit containing NMDA receptors, aryloxiranes were opened with benzylpiperidines. Phenyloxiranes 6 and (indazolyl)oxirane 15 were opened regioselectively at the position bearing the aryl moiety. Reaction of the resulting β-aminoalcohols 7 and 16 with carboxylic acids under Mitsunobu conditions (DIAD, PPh) led to rearrangement and after ester hydrolysis to the regioisomeric β-aminoalcohols 9 and 18.

Indazole as a Phenol Bioisostere: Structure-Affinity Relationships of GluN2B-Selective NMDA Receptor Antagonists.

Negative allosteric modulation of GluN2B subunit-containing NMDA receptors prevents overstimulation, resulting in neuroprotective effects. Since the phenol of prominent negative allosteric modulators is prone to rapid glucuronidation, its bioisosteric replacement by an indazole was envisaged. The key step in the synthesis was a Sonogashira reaction of non-protected iodoindazoles with propargylpiperidine derivatives.

Downstream Allosteric Modulation of NMDA Receptors by 3-Benzazepine Derivatives.

N-Methyl-D-aspartate receptors (NMDARs) composed of different splice variants display distinct pH sensitivities and are crucial for learning and memory, as well as for inflammatory or injury processes. Dysregulation of the NMDAR has been linked to diseases like Parkinson's, Alzheimer's, schizophrenia, and drug addiction. The development of selective receptor modulators, therefore, constitutes a promising approach for numerous therapeutical applications.

Discovery of RC-752, a Novel Sigma-1 Receptor Antagonist with Antinociceptive Activity: A Promising Tool for Fighting Neuropathic Pain.

Neuropathic pain (NP) is a chronic condition resulting from damaged pain-signaling pathways. It is a debilitating disorder that affects up to 10% of the world's population. Although opioid analgesics are effective in reducing pain, they present severe risks; so, there is a pressing need for non-opioid pain-relieving drugs.

Conformationally Restricted σ Receptor Antagonists from (-)-Isopulegol.

Antagonists at σ receptors have great potential for the treatment of neuropathic pain. Starting from monoterpene (-)-isopulegol (), aminodiols were obtained and transformed into bicyclic and tricyclic ligands . Aminodiols showed higher σ affinity than the corresponding bicyclic and tricyclic derivatives .

Chemical, pharmacodynamic and pharmacokinetic characterization of the GluN2B receptor antagonist 3-(4-phenylbutyl)-2,3,4,5-tetrahydro-1-3-benzazepine-1,7-diol - starting point for PET tracer development.

GluN2B-NMDA receptors play a key role in several neurological and neurodegenerative disorders. In order to develop novel negative allosteric GluN2B-NMDA receptor modulators, the concept of conformational restriction was pursued, i.e.

Discovery of Potent Cholinesterase Inhibition-Based Multi-Target-Directed Lead Compounds for Synaptoprotection in Alzheimer's Disease.

Drug development efforts that focused on single targets failed to provide effective treatment for Alzheimer's disease (AD). Therefore, we designed cholinesterase inhibition (ChEI)-based multi-target-directed ligands (MTDLs) to simultaneously target AD-related receptors. We built a library of 70 compounds, sequentially screened for ChEI, and determined σR, σR, NMDAR-GluN2B binding affinities, and P2X7R antagonistic activities.

Phenol-benzoxazolone bioisosteres of GluN2B-NMDA receptor antagonists: Unexpected rearrangement during reductive alkylation with phenylcyclohexanone.

Negative allosteric modulators of N-methyl- d-aspartate receptors containing the GluN2B subunit represent promising drug candidates for the treatment of various neurological disorders including stroke, epilepsy, and Parkinson's disease. To increase the bioavailability and GluN2B affinity, the phenol of the potent benzazepine-based inhibitor, WMS-1410 (3), was replaced bioisosterically by a benzoxazolone moiety and the phenylbutyl side chain was conformationally restricted in a phenylcyclohexyl substituent. A four-step, one-pot procedure transformed the oxazolo-benzazepine 7 into the phenylcyclohexyl derivative 11.

Phenol-Benzoxazolone bioisosteres: Synthesis and biological evaluation of tricyclic GluN2B-selective N-methyl- d-aspartate receptor antagonists.

Tricyclic tetrahydrooxazolo[4,5-h]-[3]benzazepin-9-ols 22 were designed as phenol bioisosteres of tetrahydro-3-benzazepine-1,7-diols. Key features of the synthesis are the introduction of the trifluoromethylsulfonyl and allyl protective groups at the heterocyclic N-atoms. Two methods were developed to convert the triflyl-protected ketone 16 into tricyclic alcohols 21 bearing various N-substituents.

Negative allosteric modulators of NMDA receptors with GluN2B subunit: Alanine-derived benzoxazolone bioisosteres of 2-methyl-3-benzazepine-1,7-diols.

Inspired by besonprodil, the phenol of potent negative allosteric modulators of GluN2B-N-methyl-d-aspartate (NMDA) receptors was replaced by a benzoxazolone system. To increase the similarity to the lead compounds, an additional methyl moiety was installed in the 8-position of tricyclic oxazolobenzazepines, resulting in compounds 6. The additional methyl moiety originates from alanine, which was introduced by a Mitsunobu reaction of benzoxazolylethanol 7 with N-triflyl-protected alanine methyl ester.

Synthesis and biological evaluation of conformationally restricted GluN2B ligands derived from eliprodil.

N-Methyl-d-aspartate (NMDA) receptors containing one or two GluN2B subunits play a crucial role in a variety of neurodegenerative diseases, such as Alzheimer's and Huntington's disease. In order to increase selectivity for GluN2B NMDA receptors, the piperidine ring of eliprodil (2) was conformationally restricted by introduction of an ethano bridge across C-2 and C-6 resulting in a tropane scaffold. Benzylidenetropanes 15 and 16 and benzyltropanes 17 and 18 were prepared by nucleophilic opening of enantiomerically pure phenyloxiranes 13 and 14 with racemic secondary amines (Z/E)-11 and diastereomeric mixtures (r/s)-12.

Synthesis of oxazolo-annulated 3-benzazepines designed by merging two negative allosteric NMDA receptor modulators.

To improve the metabolic stability and receptor selectivity of ifenprodil (1), the benzoxazolone moiety of besonprodil (2) and the 3-benzazepone moiety of WMS-1410 (3) were merged to obtain oxazolobenzazepines of type 4. The 5-(hydroxyethyl)benzoxazolone 7 representing the first key intermediate was prepared in four steps starting with the 4-(2-hydroxyethyl)phenol (8). Mitsunobu reaction of primary alcohol 7 with N-sulfonylated glycine esters established the necessary side chain.

Synthesis of Aminoethyl-Substituted Piperidine Derivatives as σ Receptor Ligands with Antiproliferative Properties.

A series of novel σ receptor ligands with a 4-(2-aminoethyl)piperidine scaffold was prepared and biologically evaluated. The underlying concept of our project was the improvement of the lipophilic ligand efficiency of previously synthesized potent σ ligands. The key steps of the synthesis comprise the conjugate addition of phenylboronic acid at dihydropyridin-4(1H)-ones 7, homologation of the ketones 8 and introduction of diverse amino moieties and piperidine N-substituents.

Synthesis of tropane-based σ receptor antagonists with antiallodynic activity.

Following the concept of conformational restriction to obtain high affinity σ ligands, the piperidine ring of eliprodil was replaced by the bicyclic tropane system and an exocyclic double bond was introduced. The envisaged benzylidenetropanes 9 were prepared by conversion of tropanone 10 into the racemic mixture of (Z)-14 and (E)-14. Reaction of racemate (Z)-14/(E)-14 with enantiomerically pure (R)- or (S)-configured 2-phenyloxirane provided mixtures of diastereomeric β-aminoalcohols (R,Z)-9 and (R,E)-9 as well as (S,Z)-9 and (S,E)-9, which were separated by chiral HPLC, respectively.

Synthesis of 8-aminomorphans with high KOR affinity.

2-Azabicyclo[3.3.1]nonanes (morphans) with a (3,4-dichlorophenyl)acetyl group at 2-position and a pyrrolidino moiety at 8-position were designed as conformationally restricted analogs of piperidine-based KOR agonists.

Bitopic Sigma 1 Receptor Modulators to Shed Light on Molecular Mechanisms Underpinning Ligand Binding and Receptor Oligomerization.

The sigma 1 receptor (S1R) is an enigmatic ligand-operated chaperone involved in many important biological processes, and its functions are not fully understood yet. Herein, we developed a novel series of bitopic S1R ligands as versatile tools to investigate binding processes, allosteric modulation, and the oligomerization mechanism. These molecules have been prepared in the enantiopure form and subjected to a preliminary biological evaluation, while investigations helped to rationalize the results.