PCP Binding Site Research Articles

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%).

New Amine and Aromatic Substituted Analogues of Phencyclidine: Synthesis and Determination of Acute and Chronic Pain Activities.

Phencyclidine (PCP, I) is a synthetic drug with remarkable physiological properties. PCP and its analogues exert many pharmacological activities and interact with some neurotransmitter systems in the central nervous system like particular affinity for PCP sites in NMDA receptors or dopamine uptake blocking or even both. The following research, methyl group with electron-donating and dipole moment characters was added in different positions of phenyl ring along with the substitution of benzylamine (with many pharmacological effects) instead of piperidine ring of I to produce new compounds (II-V) of this family with more analgesic activities. Analgesic activities of these new compounds were measured by tail immersion and formalin tests for acute and chronic pains, respectively. Also, the outcomes were compared with control and PCP (10 mg/kg) groups. The results indicate that compounds III, IV, and V have more acute and chronic antinociceptive effects than PCP and compound II which may be concerned with more antagonizing activities of these new painkillers for the blockage of dopamine reuptake as well as high affinity for NMDA receptors PCP binding site. It can be concluded that the benzylamine derivative of phencyclidine with a methyl group on the benzyl position on phenyl ring (V) is a more appropriate candidate to reduce acute and chronic (thermal and chemical) pains compared to other substituted phenyl analogs (II-IV) and PCP.

Structural Analysis, Molecular Modelling and Preliminary Competition Binding Studies of AM-DAN as a NMDA Receptor PCP-Site Fluorescent Ligand.

Excitotoxicity related to the dysfunction of the N-methyl-d-aspartate receptor (NMDAR) has been indicated to play an integral role in the pathophysiology of multiple disease states, including neurodegenerative disorders such as Parkinson’s disease. There is a notable gap in the market for novel NMDAR antagonists, however current methods to analyse potential antagonists rely on indirect measurements of calcium flux and hazardous radioligand binding assays. Recently, a fluorescent NMDAR ligand, N-adamantan-1-yl-dimethylamino-1-naphthalenesulfonic acid, known as AM-DAN was developed by our group. Additional studies on this ligand is necessary to evaluate its potential as a biological tool in NMDAR research. Therefore, this study was aimed at conducting structural analyses, fluorescence experiments, high-accuracy NMDAR molecular modelling and NMDAR phencyclidine (PCP) site competition binding studies using AM-DAN. Results revealed that AM-DAN has appropriate structural properties, significant fluorescent ability in various solvents and is able to bind selectively and compete for the PCP-binding site of the NMDAR. Therefore, AM-DAN holds promise as a novel fluorescent ligand to measure the affinity of prospective drugs binding at the NMDAR PCP-site and may circumvent the use of radioligands.

Modification of the 4-phenylbutyl side chain of potent 3-benzazepine-based GluN2B receptor antagonists

Excitotoxicity driven by overactivation of NMDA receptors represents a major mechanism of acute and chronic neurological and neurodegenerative disorders. Negative allosteric modulators interacting with the ifenprodil binding site of the NMDA receptor are able to interrupt this ongoing neurodamaging process. Starting from the potent 3-benzazepine-1,7-diol 4a novel NMDA receptor antagonists were designed by modification of the N-(4-phenylbutyl) side chain. With respect to developing novel fluorinated PET tracers, regioisomeric fluoroethoxy derivatives 11, 12, 14, and 15 were synthesized. Analogs 19 and 20 with various heteroaryl moieties at the end of the N-side chain were prepared by Sonogashira reaction and nucleophilic substitution. The fluoroethyl triazole 37 was obtained by 1,3-dipolar cycloaddition. In several new ligands, the flexibility of the (hetero)arylbutyl side chain was restricted by incorporation of a triple bond. The affinity towards the ifenprodil binding site was tested in an established competition assay using [3H]ifenprodil as radioligand. Introduction of a fluoroethoxy moiety at the terminal phenyl ring, replacement of the terminal phenyl ring by a heteroaryl ring and incorporation of a triple bond into the butyl spacer led to considerable reduction of GluN2B affinity. The phenol 15 (Ki = 193 nM) bearing a p-fluoroethoxy moiety at the terminal phenyl ring represents the most promising GluN2B ligand of this series of compounds. With exception of 15 showing moderate σ2 affinity (Ki = 79 nM), the interaction of synthesized 3-benzazepines towards the PCP binding site of the NMDA receptor, σ1 and σ2 receptors was rather low (Ki > 100 nM).

Hydroxymethyl bioisosteres of phenolic GluN2B-selective NMDA receptor antagonists: Design, synthesis and pharmacological evaluation

Antagonists addressing selectively NMDA receptors containing the GluN2B subunit are of particular interest for the treatment of various neurological disorders including neurodegenerative diseases. With the aim to bioisosterically replace the metabolically labile phenol of 7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-ols, several analogs were docked into the ifenprodil binding site leading to the hydroxymethyl derivatives 4 as promising candidates. They display the same binding pose as Ro 25-6981 and the same H-bond interactions with Gln110 and Glu236 within the GluN2B subunit. The phenylalkyl moieties occupy the hydrophobic pocket formed predominantly by Pro78 (GluN2B), Phe114 (GluN2B), and Tyr109 (GluN1b). Starting from o-phthalaldehyde, the hydroxymethyl derivatives 4 were prepared in a 7-step synthesis with a haloform reaction of trichloroacetophenone 7 as key step. In receptor binding studies, the phenylpropyl derivative 4a shows promising GluN2B affinity (Ki = 101 nM) and high selectivity over the PCP binding site and both σ receptor subtypes. 4a was able to inhibit the glutamate/glycine induced cytotoxicity at mouse fibroblasts with an IC50 value of 5.2 μM. It is assumed that the hydroxymethyl moiety of 4a stabilizes the closed channel conformation by an H-bond with Glu236 as does the phenolic OH moiety of 3, Ro 25-6981 and ifenprodil.

Deconstruction – reconstruction approach to analyze the essential structural elements of tetrahydro-3-benzazepine-based antagonists of GluN2B subunit containing NMDA receptors

The role of the phenolic and benzylic OH moieties for the interaction of tetrahydro-3-benzazepine-1,7-diol 3d with GluN2B subunit containing NMDA receptors was analyzed by their stepwise removal. Elimination of trifluormethanesulfinate from 10 and 13 represent the key steps in the synthesis. Removal of phenolic OH moiety led to 5-fold reduced GluN2B affinity of 4d compared with 3d. Additional removal of the benzylic OH moiety (5d) resulted in further reduced GluN2B affinity but increased σ1 and σ2 affinities. Introduction of a NO2 (6d) or NH2 moiety (7d) decreased the GluN2B affinity. 3-Benzazepin-1-ol 4i with the N-phenylcyclohexyl side chain showed the highest GluN2B affinity of this series of compounds (Ki = 2.2 nM) and, moreover, high selectivity over the PCP binding site, σ1 and σ2 receptors. In docking studies 3-benzazepines (S)-4-7 adopt the same binding poses as ifenprodil and display the same crucial interactions. Unexpectedly, the high-affinity ligands (S)-4i, (S)-4j, and (S)-6i were not able to inhibit the glutamate/glycine evoked current in two-electrode voltage clamp measurements and the cytotoxic effects of glutamate/glycine on transfected cell lines.

Design and Synthesis of Enantiomerically Pure Decahydroquinoxalines as Potent and Selective κ-Opioid Receptor Agonists with Anti-Inflammatory Activity in Vivo.

In order to develop novel κ agonists restricted to the periphery, a diastereo- and enantioselective synthesis of (4aR,5S,8aS)-configured decahydroquinoxalines 5-8 was developed. Physicochemical and pharmacological properties were fine-tuned by structural modifications in the arylacetamide and amine part of the pharmacophore as well as in the amine part outside the pharmacophore. The decahydroquinoxalines 5-8 show single-digit nanomolar to subnanomolar κ-opioid receptor affinity, full κ agonistic activity in the [35S]GTPγS assay, and high selectivity over μ, δ, σ1, and σ2 receptors as well as the PCP binding site of the NMDA receptor. Several analogues were selective for the periphery. The anti-inflammatory activity of 5-8 after topical application was investigated in two mouse models of dermatitis. The methanesulfonamide 8a containing the (S)-configured hydroxypyrrolidine ring was identified as a potent (Ki = 0.63 nM) and highly selective κ agonist (EC50 = 1.8 nM) selective for the periphery with dose-dependent anti-inflammatory activity in acute and chronic skin inflammation.

Synthesis of conformationally restricted 1,3-dioxanes to analyze the bioactive conformation of 1,3-dioxane-based σ1 and PCP receptor antagonists

The receptor binding profile of 2-phenyl-4-(aminoethyl)-1,3-dioxanes is dependent on the additional substituent in 2-position, the substituents at the amino moiety and the stereochemistry. Herein, conformationally restricted 1,3-dioxanes bearing an axially oriented phenyl moiety in 2-position were prepared and pharmacologically evaluated. Two subsequent intramolecular transacetalization reactions represent the key steps in the synthesis of the tricyclic system. The resulting alcohol 17 was transformed into amines 20–23 with axially (a-series) or equatorially oriented aminoethyl moiety (b-series). The primary amines 20a and 20b did not interact with the PCP binding site of the NMDA receptor, which is explained by the additional methylene moiety between the acetalic center and the phenyl moiety, the missing substituent at the acetalic position and/or a non-optimal three-dimensional arrangement of the pharmacophoric elements. The benzylamine 21b with an equatorially oriented aminoethyl moiety shows high σ1 affinity (Ki=5.9nM). Compared with the conformationally flexible 1,3-dioxane 5, the σ1 affinity of 21b is 3-fold and the σ1/σ2 selectivity is 5-fold increased.

The novel ketamine analog methoxetamine produces dissociative-like behavioral effects in rodents.

Methoxetamine (MXE) is a ketamine analog sold online that has been subject to widespread abuse for its dissociative and hallucinogenic effects. Previous studies have shown that MXE has high affinity for the phencyclidine (PCP) binding site located within the channel pore of the NMDA receptor (NMDAR), but little is known about its behavioral effects. Dissociative anesthetics such as ketamine and PCP produce a characteristic behavioral profile in rats that includes locomotor hyperactivity and disruption of prepulse inhibition (PPI) of acoustic startle. The goal of the present investigation was to determine whether MXE produces PCP-like effects in Sprague-Dawley rats using the PPI paradigm and the behavioral pattern monitor (BPM), which enables analyses of patterns of locomotor activity and investigatory behavior. PPI studies were conducted with several other uncompetitive NMDAR antagonists that produce dissociative effects in humans, including PCP, the S-(+) and R-(-) isomers of ketamine, and N-allylnormetazocine (NANM; SKF-10,047). MXE disrupted PPI when administered at 3 and 10mg/kg SC. The rank order of potency of MXE and the other test compounds in the PPI paradigm (PCP > MXE > S-(+)-ketamine > NANM > R-(-)-ketamine) parallels their affinities for the PCP binding site reported in the literature. When tested in the BPM, 10mg/kg MXE induced locomotor hyperactivity, reduced the number of rearings, increased the roughness of locomotor paths, and produced perseverative patterns of locomotion. Administration of PCP (2.25 and 6.75mg/kg, SC) produced a similar profile of effects in the BPM. These results indicate that MXE produces a behavioral profile similar to that of other psychotomimetic uncompetitive NMDAR antagonists. Our findings support the classification of MXE as a dissociative drug and suggest that it likely has effects and abuse potential similar to that of PCP and ketamine.

N'-3-(Trifluoromethyl)phenyl Derivatives of N-Aryl-N'-methylguanidines as Prospective PET Radioligands for the Open Channel of the N-Methyl-d-aspartate (NMDA) Receptor: Synthesis and Structure-Affinity Relationships.

N-Methyl-d-aspartate (NMDA) receptor dysfunction has been linked to several neuropsychiatric disorders, including Alzheimer's disease, epilepsy, drug addiction, and schizophrenia. A radioligand that could be used with PET to image and quantify human brain NMDA receptors in the activated "open channel" state would be useful for research on such disorders and for the development of novel therapies. To date, no radioligands have shown well-validated efficacy for imaging NMDA receptors in human subjects. In order to discover improved radioligands for PET imaging, we explored structure-affinity relationships in N'-3-(trifluoromethyl)phenyl derivatives of N-aryl-N'-methylguanidines, seeking high affinity and moderate lipophilicity, plus necessary amenability for labeling with a positron-emitter, either carbon-11 or fluorine-18. Among a diverse set of 80 prepared N'-3-(trifluoromethyl)phenyl derivatives, four of these compounds (13, 19, 20, and 36) displayed desirable low nanomolar affinity for inhibition of [(3)H](+)-MK801 at the PCP binding site and are of interest for candidate PET radioligand development.

Stereoselective synthesis and pharmacological evaluation of [4.3.3]propellan-8-amines as analogs of adamantanamines

Amantadine (1) exerts its anti-Parkinson effects by inhibition of the NMDA associated cation channel and its antiviral activity by inhibition of the M2 protein channel of influenza A viruses. Herein the synthesis, NMDA receptor affinity and anti-influenza activity of analogous propellanamines 3 are reported. The key steps in the synthesis of the diastereomeric propellanamines syn-3 and anti-3 are diastereoselective reduction of the ketone 7 with L-Selectride to give anti-11, Mitsunobu inversion of the alcohol anti-13 into syn-13, and SN2 substitution of diastereomeric mesylates syn-14 and anti-14 with NaN3. The affinity of the propellanamines syn-3 and anti-3 to the PCP binding site of the NMDA receptor is similar to that of amantadine (Ki=11μM). However, both propellanamines syn-3 and anti-3 do not exhibit activity against influenza A viruses. Compared to amantadine (1), the structurally related propellanamines syn-3 and anti-3 retain the NMDA antagonistic activity but loose the antiviral activity.

Synthesis, GluN2B affinity and selectivity of benzo[7]annulen-7-amines

Due to their beneficial side effect profile, NMDA receptor antagonists interacting selectively with the allosteric ifenprodil binding site of the GluN2B subunit are of major interest for the treatment of neurological and neurodegenerative disorders. A series of benzo[7]annulen-7-amines 6 was designed by conformational restriction of ifenprodil (1). At first the benzo[7]annulen-7-one 11 was prepared in a three-step synthesis comprising of a double Knoevenagel condensation of phthalaldehyde (7) with dimethyl 3-oxoglutarate (8), hydrogenation of 9 and saponification/decarboxylation of 10. Reductive amination of the ketone 11 with primary amines and NaBH(OAc)3 led to the secondary amines 6a–d, cis-6h and trans-6i. The tertiary amines 6e–g were obtained by SN2-substitution of the nosylate 13. Although H-bond forming substituents in 2- and 5-position are missing, the amines 6 exhibit high affinity towards GluN2B containing NMDA receptors. A distance of four to five bond lengths between the basic amino moiety and the phenyl ring in the side chain appears to be optimal for high GluN2B affinity. The phenylcyclohexylamine cis-6h and the 4-benzylpiperidine 6g show the highest GluN2B affinities (Ki=2.3nM and 2.9nM, respectively). With respect to selectivity against the PCP binding site, σ1 and σ2 receptors the phenylpiperazine 6f is the most promising GluN2B antagonist.

Enantiomerically Pure 1,3-Dioxanes as Highly Selective NMDA and σ1 Receptor Ligands

We synthesized and investigated the NMDA and σ₁ receptor affinity of enantiomerically pure 2-(2-phenyl-1,3-dioxan-4-yl)ethanamines 17-26. The primary amines (R,R)-18-20 with an axially oriented phenyl moiety in position 2 interacted with high enantioselectivity (eudismic ratios 70-130) and high affinity (K(i)((R,R)-19) = 13 nM) with the PCP binding site of the NMDA receptor. Introduction of an N-benzyl moiety led to potent σ₁ ligands including compound (S,R)-22 (K(i) = 6 nM) with an equatorially oriented phenyl moiety in position 2.

Chronic anti-phencyclidine monoclonal antibody therapy decreases phencyclidine-induced in utero fetal mortality in pregnant rats

Illicit drug use during pregnancy is a serious social and public health problem inflicting an array of deleterious effects on both mother and offspring. We investigated the hypothesis that a murine anti-phencyclidine (PCP) monoclonal antibody (mAb6B5; KD=1.3nM) can safely protect mother and fetus from PCP-induced adverse health effects in pregnant rats. Pregnant Sprague–Dawley rats (n=4–5) were intravenously administered bolus injections of PCP (1mg/kg) on multiple days during pregnancy. They were also chronically treated with anti-PCP mAb6B5 at 45mg/kg as a PCP antagonist. This dose provided one mAb–PCP binding site for every four PCP molecules. Therapeutic and safety study endpoints included pregnancy outcome (litter size, number of live vs. dead pups), maternal hemodynamic status and locomotor activity. Maternal hemodynamic changes (i.e., blood pressure and heart rate) and locomotor activity were measured in dams from gestation days 6–21 (one day antepartum) using a radiotelemetry-tracking device with a femoral arterial pressure catheter. This mAb6B5 treatment regimen significantly (p=0.008) reduced the number of PCP-induced in utero fetal deaths (odds ratio=3.2; 95%CI 1.3 to 7.9) and significantly (p<0.05) reduced acute PCP-induced maternal locomotor effects in the second trimester. Maternal hemodynamic responses to PCP were not significantly affected by mAb6B5 treatment. In conclusion, these data suggest that anti-PCP mAb treatments administered during pregnancy can safely protect a mother and her fetus(es) from PCP-related morbidity and mortality even when the mAb dose is too low to significantly prevent other PCP-induced maternal pharmacological effects.

Combination of Two Pharmacophoric Systems: Synthesis and Pharmacological Evaluation of Spirocyclic Pyranopyrazoles with High σ1 Receptor Affinity

The novel class of spirocyclic σ(1) ligands 3 (6',7'-dihydro-1'H-spiro[piperidine-4,4'-pyrano[4,3-c]pyrazoles]) was designed by the combination of the potent σ(1) ligands 1 and 2 in one molecule. Thorough structure affinity relationships were derived by the variation of the substituents in position 1', 1, and 6'. Whereas the small electron rich methylpyrazole heterocycle was less tolerated by the σ(1) receptor protein, the introduction of a phenyl substituent instead of the methyl group led to ligands with a high σ(1) affinity. It is postulated that the additional phenyl substituent occupies a previously unrecognized hydrophobic region of the σ(1) receptor resulting in additional lipophilic interactions. The spirocyclic pyranopyrazoles are very selective against the σ(2) subtype, the PCP binding site of the NMDA receptor, and further targets. Despite high σ(1) affinity, the cyclohexylmethyl derivative 17i (K(i) (σ(1)) = 0.55 nM) and the isopentenyl derivative 17p (K(i) (σ(1)) = 1.6 nM) showed only low antiallodynic activity in the capsaicin assay.

Synthesis and Preliminary Biochemical Evaluation of Novel Derivatives of PCP

(±)-Trans-Ph/Et and (±)-cis-Ph/Et 1-(2-ethyl-1-phenylcyclohexyl)piperidine were synthesized from 2-ethylcyclohexanone. In contrast to the corresponding trans-substituted 2-methyl compound which is 5x more potent than PCP, the trans-2-ethyl derivative has a 75x lower affinity for the PCP binding site. The cis-2-ethyl isomer is inactive like the cis-2-methyl derivative. (±)-1-(1- Phenylcyclohexyl)-2-methylpiperidine is almost as active as the parent PCP. Reduction of the aromatic ring or quaternization of the piperidine in PCP reduces the affinity for the PCP site. Keywords: Phencyclidine, Conformations, NMDA receptor, PCP binding site, Bruylants reaction, Ritter reaction

Enantioselective Synthesis of a 2,2-Disubstituted Tetrahydro-3- benzazepine as Novel NMDA Receptor Antagonist

The tricyclic oxazolidines trans-4 and cis-4 were interconverted upon treatment with allyltrimethylsilane/ TiCl4. The oxazolidine trans-4 was diastereoselectively reacted with PhMgBr to yield the 4,4-disubstituted 3-benzazepinone 6, along with two side products. An X-ray crystal structure analysis of 6 proved the (R)-configuration of the stereogenic center C-4 and thus the retention of configuration. Reduction of 6 with AlCl3/LiAlH4 (1/3) followed by hydrogenolysis with H2, Pd/C resulted in the formation of enantiomerically pure 2-methyl-2-phenyl-tetrahydro-3-benzazepine 11 which has a moderate affinity (Ki = 496 nM) to the PCP binding site of the NMDA receptor.

Asymmetric Synthesis of Enantiomerically Pure 2-Substituted Tetrahydro-3-benzazepines and Their Affinity to σ1 Receptors

A very short asymmetric synthesis of enantiomerically pure 2-substituted tetrahydro-3-benzazepines is described. First, 3-phenyl-2,3,11,11a-tetrahydro[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-ones 3a-d and 4a-d were synthesized by condensation of 2-(2-oxoalkyl)phenylacetic acids 1a-d with (R)-phenylglycinol (2). With the exception of the 11a-phenyl derivatives 3d/4d (ratio 91:9), the ratio of the diastereomeric 11a-alkyl derivatives 3a-c/4a-c was almost 50:50. The configuration of the newly formed chiral center in position 11a was proved by NOE experiments as well as X-ray crystal structure analysis. The reduction of the oxazolo[2,3-b][3]benzazepin-5(6H)-ones trans-3 and cis-4 with AlCl(3)/LiAlH(4) (1:3) took place with retention of configuration and yielded 2,3-disubsituted tetrahydro-3-benzazepines 10 and11. In the final step, removal of the N-(2-hydroxy-1-phenylethyl) residue from 10 and 11 by hydrogenolysis provided four pairs of enantiomerically pure 2-substituted tetrahydro-3-benzazepines 12a-d and ent-12a-d, which were tested for their sigma(1), sigma(2), and NMDA receptor affinities. The 2-butyl and the 2-phenyl derivatives 12c and 12d show very high sigma(1) affinity with K(i) values of 16 and 50 nM, respectively. The eudismic ratios are greater than 50, reflecting highly stereoselective interaction with the sigma(1) receptor. Both sigma(1) ligands are very selective against the sigma(2) subtype and the PCP binding site of the NMDA receptor.

Asymmetric Synthesis of 1‐Substituted Tetrahydro‐3‐benzazepines as NMDA Receptor Antagonists

AbstractA novel asymmetric synthesis of 1‐substituted tetrahydro‐3‐benzazepines (R)‐15 and (S)‐15 has been performed. Starting with o‐phenylenediacetic acid (1) and (R)‐phenylglycinol as chiral auxiliary the tricyclic oxazololactam (3R)‐10 was synthesized as key intermediate. Deprotonation of (3R)‐10 with LDA led to an enolate, which was trapped with different arylalkyl and alkyl halides to yield 6‐substituted oxazololactams (6R)‐12 with high diastereoselectivity. The best diastereomeric ratio (about 95:5) was achieved with benzyl bromide and 2‐methylbenzyl bromide. The diastereomers were separated using preparative HPLC to obtain diastereomerically pure (6R)‐12. Two successive reduction procedures (LiAlH4/AlCl3, then NH4HCO2, Pd/C) led to enantiomerically pure 1‐substituted tetrahydro‐3‐benzazepines (R)‐15. Starting the synthesis with (R)‐ and (S)‐phenylglycinol provided both enantiomers (R)‐15 and (S)‐15, which were investigated for their affinity to the PCP binding site of the NMDA receptor. The NMDA receptor affinities of the enantiomeric pairs are very similar. With a Ki value of 1.66 μM the 2‐methylbenzyl‐substituted derivative (R)‐15c displays the highest NMDA receptor affinity in this series. (© Wiley‐VCH Verlag GmbH &amp; Co. KGaA, 69451 Weinheim, Germany, 2007)

Affinity of 1-aryl-1,2,3,4-tetrahydroisoquinoline derivatives to the ion channel binding site of the NMDA receptor complex

A series of 1-aryl-1,2,3,4-tetrahydroisoquinoline and 8-methyl-1-aryl-1,2,3,4-tetrahydroisoquinoline derivatives was evaluated for affinity to the PCP binding site of the NMDA receptor complex. The ( S)-configurated tetrahydroisoquinoline derivative ( S)- 4e·HCl bearing a 2-methylphenyl substituent in position 1 of the heterocyclic ring system and a methyl group in position 8 was found to exhibit the highest affinity among the derivatives with a K i-value of 0.0374 μM. In addition, this compound shows a remarkable enantioselectivity of binding by being almost 90 times more potent than the corresponding ( R)-enantiomer ( R)- 4e·HCl. Additionally, a convenient and efficient synthetic approach to racemic 1-aryl-1,2,3,4-tetrahydroisoquinoline derivatives is described.