Σ1 Receptor Affinity Research Articles

Synthesis and structure-affinity relationships of spirocyclic σ1 receptor ligands with tetrahydropyran scaffold

The σ1 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 σ1 receptor ligands with different substituents in 4- and 9-position were synthesized and investigated for their σ1 receptor affinity and selectivity over related targets. The σ1 affinity of the ligands was correlated with their lipophilicity (logD7.4 value) giving insight into their lipophilic ligand efficiency (LLE). The (pyridin-3-yl)methyl derivative 5i showed a promising balance of high σ1 affinity (Ki(σ1) = 3.9 nM) and selectivity (> 250-fold) as well as high LLE of 5.8. 5i has a high plasma protein binding (89%) and promising metabolic stability in the presence of mouse liver microsomes and NADPH (83% intact after 90 min). Increasing the size of the piperidine ring of the spirocyclic ligands 5 to an azepane ring led to considerably increased σ1 affinity (Ki(5a) = 1.2 nM, Ki(23a) = 0.42 nM) and selectivity over σ2 receptors (5a: 45-fold, 23a: 150-fold).

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. This novel morphan synthesis allowed the modification of the bicyclic system at three positions resulting in 26 diverse morphans. Various primary amines led to morphans 8-13 with different N-substituents. Acylation or water elimination followed by hydrogenation led to esters 15 and 16 or the morphan 18 without a hydroxy moiety. The benzylidenemorphans 25a and 26a were prepared by condensation of the ketones 11a and 12a with benzaldehyde. Finally, the α-methylene ketone of 11a and 12a was exploited to obtain indolomorphans, quinolinomorphans, pyrimidinomorphans and pyrazolomorphans. Affinity of the novel morphans at opioid receptors MOR, DOR and KOR could not be detected. However, the indolomorphan 19 and the quinolinomorphan 22 showed nanomolar σ1 receptor affinity (Ki=58 nM and 20 nM).

18F]Fluspidine-A PET Tracer for Imaging of σ1 Receptors in the Central Nervous System.

σ1 receptors play a crucial role in various neurological and neurodegenerative diseases including pain, psychosis, Alzheimer's disease, and depression. Spirocyclic piperidines represent a promising class of potent σ1 receptor ligands. The relationship between structural modifications and σ1 receptor affinity and selectivity over σ2 receptors led to the 2-fluoroethyl derivative fluspidine (2, Ki = 0.59 nM). Enantiomerically pure (S)-configured fluspidine ((S)-2) was prepared by the enantioselective reduction of the α,β-unsaturated ester 23 with NaBH4 and the enantiomerically pure co-catalyst (S,S)-24. The pharmacokinetic properties of both fluspidine enantiomers (R)-2 and (S)-2 were analyzed in vitro. Molecular dynamics simulations revealed very similar interactions of both fluspidine enantiomers with the σ1 receptor protein, with a strong ionic interaction between the protonated amino moiety of the piperidine ring and the COO- moiety of glutamate 172. The 18F-labeled radiotracers (S)-[18F]2 and (R)-[18F]2 were synthesized in automated syntheses using a TRACERlab FX FN synthesis module. High radiochemical yields and radiochemical purity were achieved. Radiometabolites were not found in the brains of mice, piglets, and rhesus monkeys. While both enantiomers revealed similar initial brain uptake, the slow washout of (R)-[18F]2 indicated a kind of irreversible binding. In the first clinical trial, (S)-[18F]2 was used to visualize σ1 receptors in the brains of patients with major depressive disorder (MDD). This study revealed an increased density of σ1 receptors in cortico-striato-(para)limbic brain regions of MDD patients. The increased density of σ1 receptors correlated with the severity of the depressive symptoms. In an occupancy study with the PET tracer (S)-[18F]2, the selective binding of pridopidine at σ1 receptors in the brain of healthy volunteers and HD patients was shown.

Relationships between the structure of spiro[[2]benzopyran-1,1′-cyclohexan]-4′-amines and their σ1 receptor affinity and selectivity

A set of 31 secondary and tertiary amines of type 5 was synthesized by reductive amination of ketones 6 and 22–24 with amines and NaBH(OAc)3. Usually, cis-configured amines display higher σ1 affinity than trans-configured analogs. Elongation of the distance between the amino moiety and the terminal phenyl ring from one to three CH2 moieties increased the σ1 affinity. Tertiary amines with one small N-substituent are well tolerated by the σ1 receptor. Within this class of compounds, the cyclohexylpiperazines trans-21a (Ki(σ1) = 6.3 nM) and cis-21b (Ki(σ1) = 4.4 nM) show very high σ1 affinity and selectivity over related receptors (σ2 receptor, MOR, DOR, KOR). On the other hand, the cis-configured p-fluorophenylpiperazine cis-20b was identified as high-affinity σ2 ligand (Ki(σ2) = 11 nM) with considerable selectivity over σ1 receptor, MOR, DOR and KOR. Very high MOR affinity (Ki = 2.3 nM), but only moderate affinity towards both σ receptor subtypes was detected for the cis-configured piperidine cis-17b without aryl moiety at the piperidine ring. Thus, cis-17b represents a novel MOR chemotype with high MOR affinity and high selectivity over both σ receptors, DOR and KOR.

Diastereoselective synthesis and structure-affinity relationships of σ1 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. DFT calculations explain the mechanism of this transformation as concerted Diels-Alder reaction (functionals B3LYP and TPSS) or double (aza)-Michael addition (functionals PBE and wB97X-D). After separation of the diastereomeric spirocyclic products 8 and 17-20, LiAlH4 reduction provided the spirocyclic hydroxymethyl piperidines 21a,b-25a,b showing low nanomolar σ1 affinity (Ki < 100 nM). trans-Configured ligands (a-series) showed higher or equal σ1 affinity and higher selectivity over σ2 receptors and GluN2B-NMDA receptors than their cis-configured analogs (b-series). The additional hydroxymethyl moiety brings the log D7.4 value in a promising range. The high σ1 affinity (Ki = 3.6 nM) and the low lipophilicity result in the highest lipophilic ligand efficiency for the dispiro compound 23a (LLE = 6.0). The spirocyclic compounds reported herein and in particular the dispiro compound 23a demonstrate that ligands containing a large number of sp3 C-atoms possess favorable pharmacological (σ1 receptor affinity, receptor selectivity) and physicochemical properties (log D7.4 value) resulting in promising LLE.

Discovery of potent dual ligands for dopamine D4 and σ1 receptors

During our work on exploration of molecules with some piperidine-triazole scaffolds, we realized that our compounds display chemical similarity with some σ, as well as dopaminergic receptor ligands. Here we show that this series of molecules has indeed strong affinity both for σ1 and dopamine D4 receptors. Moreover, they appear selective towards σ2, dopamine paralogues D1, D2, D3 and D5 receptors and hERG channel. Extensive molecular dynamics with our lead compound AVRM-13 were carried out on σ1, supporting agonist activity of the ligand. Unexpectedly, several observations suggested the existence of a cation binding domain, a probable regulatory site for calcium.

Screening of σ2 Receptor Ligands and In Vivo Evaluation of 11C-Labeled 6,7-Dimethoxy-2-[4-(4-methoxyphenyl)butan-2-yl]-1,2,3,4-tetrahydroisoquinoline for Potential Use as a σ2 Receptor Brain PET Tracer

In this study, a panel of 46 compounds containing five different scaffolds known to have high σ2 receptor affinity were screened. 6,7-Dimethoxy-2-[4-(4-methoxyphenyl)butan-2-yl]-1,2,3,4-tetrahydroisoquinoline [(±)-7] (Ki for σ1 = 48.4 ± 7.7 nM, and Ki for σ2 = 0.59 ± 0.02 nM) and its desmethyl analogue, (±)-8 (Ki for σ1 = 108 ± 35 nM, and Ki for σ2 = 4.92 ± 0.59 nM), showed excellent binding affinity and subtype selectivity for σ2 receptors. In vitro cell binding indicated that σ2 receptor binding of [11C]-(±)-7 and [11C]-(±)-8 was dependent on TMEM97 protein expression. In PET studies, the peak brain uptake of [11C]-(±)-7 (8.28 ± 2.52%ID/cc) was higher than that of [11C]-(±)-8 (4.25 ± 0.97%ID/cc) with specific distribution in the cortex and hypothalamus. Brain uptake or tissue binding was selectively inhibited by ligands with different σ2 receptor binding affinities. The results suggest [11C]-(±)-7 can be used as a PET radiotracer for imaging the function of σ2 receptors in central nervous system disorders.

Synthesis and characterization of the two enantiomers of a chiral sigma-1 receptor radioligand: (S)-(+)- and (R)-(-)-[18F]FBFP

Racemic [18F]FBFP ([18F]1) proved to be a potent σ1 receptor radiotracer with superior imaging properties. The pure enantiomers of unlabeled compounds (S)- and (R)-1 and the corresponding iodonium ylide precursors were synthesized and characterized. The two enantiomers (S)-1 and (R)-1 exhibited comparable high affinity for σ1 receptors and selectivity over σ2 receptors. The Ca2+ fluorescence assay indicated that (R)-1 behaved as an antagonist and (S)-1 as an agonist for σ1 receptors. The 18F-labeled enantiomers (S)- and (R)-[18F]1 were obtained in >99% enantiomeric purity from the corresponding enantiopure iodonium ylide precursors with radiochemical yield of 24.4% ± 2.6% and molar activity of 86–214 GBq/µmol. In ICR mice both (S)- and (R)-[18F]1 displayed comparable high brain uptake, brain-to-blood ratio, in vivo stability and binding specificity in the brain and peripheral organs. In micro-positron emission tomography (PET) imaging studies in rats, (S)-[18F]1 exhibited faster clearance from the brain than (R)-[18F]1, indicating different brain kinetics of the two enantiomers. Both (S)- and (R)-[18F]1 warrant further evaluation in primates to translate a single enantiomer with more suitable kinetics for imaging the σ1 receptors in humans.

Synthesis of Aminoethyl-Substituted Piperidine Derivatives as σ1 Receptor Ligands with Antiproliferative Properties.

A series of novel σ1 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 σ1 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. 1‐Methylpiperidines showed particular high σ1 receptor affinity and selectivity over the σ2 subtype, whilst piperidines with a proton, a tosyl moiety or an ethyl moiety exhibited considerably lower σ1 affinity. Molecular dynamics simulations with per‐residue binding free energy deconvolution demonstrated that different interactions of the basic piperidine‐N‐atom and its substituents (or the cyclohexane ring) with the lipophilic binding pocket consisting of Leu105, Thr181, Leu182, Ala185, Leu186, Thr202 and Tyr206 are responsible for the different σ1 receptor affinities. Recorded logD7.4 and calculated clogP values of 4a and 18a indicate low lipophilicity and thus high lipophilic ligand efficiency. Piperidine 4a inhibited the growth of human non‐small cell lung cancer cells A427 to a similar extent as the σ1 antagonist haloperidol. 1‐Methylpiperidines 20a, 21a and 22a showed stronger antiproliferative effects on androgen negative human prostate cancer cells DU145 than the σ1 ligands NE100 and S1RA.

Discovery and development of brain-penetrant 18F-labeled radioligands for neuroimaging of the sigma-2 receptors

We have discovered and synthesized a series of indole-based derivatives as novel sigma-2 (σ2) receptor ligands. Two ligands with high σ2 receptor affinity and subtype selectivity were then radiolabeled with F-18 in good radiochemical yields and purities, and evaluated in rodents. In biodistribution studies in male ICR mice, radioligand [18F]9, or 1-(4-(5,6-dimethoxyisoindolin-2-yl)butyl)-4-(2-[18F]fluoroethoxy)-1H-indole, was found to display high brain uptake and high brain-to-blood ratio. Pretreatment of animals with the selective σ2 receptor ligand CM398 led to significant reductions in both brain uptake (29%–54%) and brain-to-blood ratio (60%–88%) of the radioligand in a dose-dependent manner, indicating high and saturable specific binding of [18F]9 to σ2 receptors in the brain. Further, ex vivo autoradiography in male ICR mice demonstrated regionally heterogeneous specific binding of [18F]9 in the brain that is consistent with the distribution pattern of σ2 receptors. Dynamic positron emission tomography imaging confirmed regionally distinct distribution and high levels of specific binding for [18F]9 in the rat brain, along with appropriate tissue kinetics. Taken together, results from our current study indicated the novel radioligand [18F]9 as the first highly specific and promising imaging agent for σ2 receptors in the brain.

Chemoenzymatic synthesis of 2,6-disubstituted tetrahydropyrans with high σ1 receptor affinity, antitumor and analgesic activity.

1,3-Dioxanes 1 and cyclohexanes 2 bearing a phenyl ring and an aminoethyl moiety in 1,3-relationship to each other represent highly potent σ1 receptor antagonists. In order to increase the chemical stability of the acetalic 1,3-dioxanes 1 and the polarity of the cyclohexanes 2, tetrahydropyran derivatives 3 equipped with the same substituents were designed, synthesized and pharmacologically evaluated. The key step of the synthesis was a lipase-catalyzed enantioselective acetylation of the alcohol (R)-5 leading finally to enantiomerically pure test compounds 3a-g. With respect to σ1 receptor affinity and selectivity over a broad range of related (σ2, PCP binding site) and further targets, the enantiomeric benzylamines 3a and cyclohexylmethylamines 3b represent the most promising drug candidates of this series. However, the eudismic ratio for σ1 binding is only in the range of 2.5-3.3. Classical molecular dynamics (MD) simulations confirmed the same binding pose for both the tetrahydropyran 3 and cyclohexane derivatives 2at the σ1 receptor, according to which: i) the protonated amino moiety of (2S,6R)-3a engages the same key polar interactions with Glu172 (ionic) and Phe107 (π-cation), ii) the lipophilic parts of (2S,6R)-3a are hosted in three hydrophobic regions of the σ1 receptor, and iii) the O-atom of the tetrahydropyran derivatives 3 does not show a relevant interaction with the σ1 receptor. Further in silico evidences obtained by the application of free energy perturbation and steered MD techniques fully supported the experimentally observed difference in receptor/ligand affinities. Tetrahydropyrans 3 require a lower dissociative force peak than cyclohexane analogs 2. Enantiomeric benzylamines 3a and cyclohexylmethylamines 3b were able to inhibit the growth of the androgen negative human prostate cancer cell line DU145. The cyclohexylmethylamine (2S,6R)-3b showed the highest σ1 affinity (Ki(σ1)=0.95nM) and the highest analgesic activity invivo (67%).

Synthesis and evaluation of new 1-oxa-8-azaspiro[4.5]decane derivatives as candidate radioligands for sigma-1 receptors

We report the design, synthesis, and evaluation of a series of 1-oxa-8-azaspiro[4.5]decane and 1,5-dioxa-9-azaspiro[5.5]undecane derivatives as selective σ1 receptor ligands. All seven ligands exhibited nanomolar affinity for σ1 receptors (Ki(σ1) = 0.47 – 12.1 nM) and moderate selectivity over σ2 receptors (Ki(σ2)/ Ki(σ1) = 2 – 44). Compound 8, with the best selectivity among these ligands, was selected for radiolabeling and further evaluation. Radioligand [18F]8 was prepared via nucleophilic 18F-substitution of the corresponding tosylate precursor, with an overall isolated radiochemical yield of 12–35%, a radiochemical purity of greater than 99%, and molar activity of 94 – 121 GBq/μmol. Biodistribution studies of [18F]8 in mice demonstrated high initial brain uptake at 2 min. Pretreatment with SA4503 resulted in significantly reduced brain-to-blood ratio (70% − 75% at 30 min). Ex vivo autoradiography in ICR mice demonstrated high accumulation of the radiotracer in σ1 receptor-rich brain areas. These findings suggest that [18F]8 could be a lead compound for further structural modifications to develop potential brain imaging agents for σ1 receptors.

Piperidine propionamide as a scaffold for potent sigma-1 receptor antagonists and mu opioid receptor agonists for treating neuropathic pain

We designed and synthesized a novel series of piperidine propionamide derivatives as potent sigma-1 (σ1) receptor antagonists and mu (μ) opioid receptor agonists, and measured their affinity for σ1 and μ receptors in vitro through binding assays. The basic scaffold of the new compounds contained a 4-substituted piperidine ring and N-aryl propionamide. Compound 44, N-(2-(4-(4-fluorobenzyl) piperidin-1-yl) ethyl)-N-(4-methoxy-phenyl) propionamide, showed the highest affinity for σ1 receptor (Ki σ1 = 1.86 nM) and μ receptor (Ki μ = 2.1 nM). It exhibited potent analgesic activity in the formalin test (ED50 = 15.1 ± 1.67 mg/kg) and had equivalent analgesic effects to S1RA (σ1 antagonist) in a CCI model. Therefore, Compound 44, which has mixed σ1/μ receptor profiles, may be a potential candidate for treating neuropathic pain.

Pharmacological characterization of high-affinity σ1 receptor ligands with spirocyclic thienopyran and thienofuran scaffold.

In this study, the pharmacological properties of six spirocyclic piperidines 1-6 showing very high σ1 receptor affinity (Ki =0.2-16nm) were investigated. In vitro receptor binding studies, retinal ganglion assay and in vivo capsaicin assay were used to determine the affinity, selectivity and activity. Influence on human tumour cell growth (cell lines A427, LCLC-103H, 5637 and DAN-G) was determined in different assays. The effect on the ergosterol and cholesterol biosynthesis was determined by GLC/MS analysis. Receptor binding studies demonstrated high selectivity for the σ1 receptor. The increased Ca2+ influx mediated by 2 and the analgesic activity of 1, 4, 5 and 6 confirm σ1 receptor antagonistic activity. Inhibition of human tumour cell growth further supports the σ1 antagonistic effects. Treatment of A427 tumour cells with 2 led to cell detachment and cell degradation. Whereas the ergosterol biosynthesis was not affected, the sterol C14-reductase, a key enzyme in the cholesterol biosynthesis, was weakly inhibited. Due to the high selectivity, off-target effects are not expected. The antiallodynic activity underlines the clinical potential of the spirocyclic piperidines for the treatment of neuropathic pain. Due to the antiproliferative activity, the spirocyclic σ1 antagonists represent promising antitumour agents.

High-affinity sigma-1 (σ1) receptor ligands based on the σ1 antagonist PB212.

Aim: The σ1 receptor is a druggable target involved in many physiological processes and diseases. To clarify its physiology and derive therapeutic benefit, nine analogs based on the σ1 antagonist PB212 were synthesized replacing the 4-methylpiperidine with basic moieties of varying size and degree of conformational freedom. Results & methodology: 3-Phenylpyrrolidine, 4-phenylpiperidine or granatane derivatives displayed the highest affinity (Ki.#x00A0;=0.12, 0.31 or 1.03nM). Calcium flux assays in MCF7σ1 cells indicated that the highest σ1 receptor affinity are σ1 antagonists. Molecular models provided a structural basis for understanding the σ1 affinity and functional activity of the analogs and incorporated Glennon's σ1 pharmacophore model. Conclusion: Herein, we identify new compounds exploitable as therapeutic drug leads or as tools to study σ1 receptor physiology.

Structure-Affinity Relationships of Fluorinated Spirocyclic σ2 Receptor Ligands with an Exocyclic Benzylamino Moiety.

To identify a potent and selective σ2 receptor ligand appropriate for development as a positron emission tomography (PET) tracer, several fluorinated analogues of the spirocyclic lead compounds trans- and cis-6 (N-(2,4-dimethylbenzyl)-3-methoxy-3,4-dihydrospiro[[2]benzopyran-1,1'-cyclohexan]-4'-amine) were designed. In multistep syntheses, a fluorine atom was introduced directly or as a 2-fluoroethoxy moiety on the 2-benzopyran scaffold, on the dimethylbenzylamino moiety, or on the central amino moiety. The σ1 and σ2 receptor affinity was determined in receptor binding studies with radioligands. With respect to σ2 affinity and σ2 /σ1 selectivity, cis-N-(2,4-dimethylbenzyl)-5-fluoro-3-methoxy-3,4-dihydrospiro[[2]benzopyran-1,1'-cyclohexan]-4'-amine (cis-15 c, Ki (σ2 )=51 nm) and cis-N-[4-(fluoromethyl)-2-methylbenzyl]-3-methoxy-3,4-dihydrospiro[[2]benzopyran-1,1'-cyclohexan]-4'-amine (cis-28 e, Ki (σ2 )=57 nm) are the most promising ligands. The combination of both structural elements in one molecule, cis-N-[4-(fluoromethyl)-2-methylbenzyl]-5-fluoro-3-methoxy-3,4-dihydrospiro[[2]benzopyran-1,1'-cyclohexan]-4'-amine (cis-28 c: Ki (σ2 )=874 nm), resulted in decreased σ2 and σ1 affinity. Methylation of secondary amines led to three tertiary methylamines with moderate affinity for both σ receptor subtypes.

18 F-Labeled benzylpiperazine derivatives as highly selective ligands for imaging σ1 receptor with positron emission tomography.

We report the design, synthesis, and evaluation of a new series of benzylpiperazine derivatives as selective σ1 receptor ligands. All seven ligands possessed low nanomolar affinity for σ1 receptors (Ki (σ1 )=0.31-4.19 nM) and high subtype selectivity (Ki (σ2 )/Ki (σ1 )=50-2448). The fluoroethoxy analogues also exhibited high selectivity toward the vesicular acetylcholine transporter (Ki (VAChT)/Ki (σ1 )=99-18252). The corresponding radiotracers [18 F]13, [18 F]14, and [18 F]16 with high selectivity (Ki (σ2 )/Ki (σ1 )>100, Ki (VAChT)/Ki (σ1 )>1000) were prepared in 42% to 55% radiochemical yields (corrected for decay), greater than 99% radiochemical purity (RCP), and molar activity of about 120GBq/μmol at the end of synthesis (EOS). All three radiotracers showed high initial brain uptake in mouse (8.37-11.48% ID/g at 2min), which was not affected by pretreatment with cyclosporine A, suggesting that they are not substrates for permeability-glycoprotein (P-gp). Pretreatment with SA4503 or haloperidol resulted in significantly reduced brain uptake (35%-62% decrease at 30min). In particular, [18 F]16 displayed high brain-to-blood ratios and high in vivo metabolic stability. Although it may not be an optimal neuroimaging agent because of its slow kinetics in the mouse brain, [18 F]16 can serve as a lead compound for further structural modifications to explore new potential radiotracers for σ1 receptors.

Synthesis and Structure-Affinity Relationships of Spirocyclic Benzopyrans with Exocyclic Amino Moiety.

σ1 and/or σ2 receptors play a crucial role in pathological conditions such as pain, neurodegenerative disorders, and cancer. A set of spirocyclic cyclohexanes with diverse O-heterocycles and amino moieties (general structure III) was prepared and pharmacologically evaluated. In structure-activity relationships studies, the σ1 receptor affinity and σ1:σ2 selectivity were correlated with the stereochemistry, the kind and substitution pattern of the O-heterocycle, and the substituents at the exocyclic amino moiety. cis-configured 2-benzopyran cis-11b bearing a methoxy group and a tertiary cyclohexylmethylamino moiety showed the highest σ1 affinity ( Ki = 1.9 nM) of this series of compounds. In a Ca2+ influx assay, cis-11b behaved as a σ1 antagonist. cis-11b reveals high selectivity over σ2 and opioid receptors. The interactions of the novel σ1 ligands were analyzed on the molecular level using the recently reported X-ray crystal structure of the σ1 receptor protein. The protonated amino moiety forms a persistent salt bridge with E172. The spiro[benzopyran-1,1'-cyclohexane] scaffold and the cyclohexylmethyl moiety occupy two hydrophobic pockets. Exchange of the N-cyclohexylmethyl moiety by a benzyl group led unexpectedly to potent and selective μ-opioid receptor ligands.

Morphing of Ibogaine: A Successful Attempt into the Search for Sigma-2 Receptor Ligands.

Ibogaine is a psychoactive indole alkaloid with high affinity for several targets including the σ2 receptor. Indeed, extensive data support the involvement of the σ2 receptor in neurological disorders, including Alzheimer’s disease, schizophrenia, alcohol abuse and pain. Due to its serious side effects which prevent ibogaine from potential clinical applications, novel ibogaine derivatives endowed with improved σ2 receptor affinity may be particularly beneficial. With the purpose to facilitate the investigation of iboga alkaloid derivatives which may serve as templates for the design of selective σ2 receptor ligands, here we report a deconstruction study on the ibogaine tricyclic moiety and a successive scaffold-hopping of the indole counterpart. A 3D-QSAR model has been applied to predict the σ2 pKi values of the new compounds, whereas a molecular docking study conducted upon the σ2 receptor built by homology modeling was used to further validate the best-scored molecules. We eventually evaluated pinoline, a carboline derivative, for σ2 receptor affinity through radioligand binding assay and the results confirmed the predicted high µM range of affinity and good selectivity. The obtained results could be helpful in the drug design process of new ibogaine simplified analogs with improved σ2 receptor binding capabilities.

Synthesis of 3-aza[4.4.3]propellanes with high σ1 receptor affinity

In order to obtain rigid σ1 receptor ligands with defined orientation of pharmacophoric elements, the azapropellane scaffold was chosen. Schmidt rearrangement of propellan-8-ones 6 and 10 provided 3-azapropellan-4-ones 7 and 11. Benzylation of the secondary lactams 7 and 11 followed by LiAlH4 reduction furnished the azapropellanes 4a and 4c, respectively. A second hydrophobic element was introduced by transformation of the alcohols 4a into carbamates 4b. The σ1 affinity of the azapropellanes 4 is strongly dependent on the stereochemistry and the substitution pattern in 12-position. anti-configured azapropellanes anti-4a and anti-4b show higher σ1 affinity than their syn-configured counterparts syn-4a and syn-4b. Conversion of the alcohol anti-4a into the carbamate anti-4b led to increased σ1 affinity, but complete removal of the 12-substituent resulted in the highest σ1 affinity (Ki(4c) = 17 nM). It can be concluded that the propellane scaffold alone is able to form strong lipophilic interactions and stabilize the ligand–σ1 receptor complex as does usually the primary hydrophobic region.