PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Bioorg Med Chem. Author manuscript; available in PMC 2017 August 15.
Published in final edited form as:
PMCID: PMC5060005
NIHMSID: NIHMS795546

Design and Synthesis of Dual 5-HT1A and 5-HT7 Receptor Ligands

Abstract

5-HT1A and 5-HT7 receptors have been at the center of discussions recently due in part to their major role in the etiology of major central nervous system diseases such as depression, sleep disorders, and schizophrenia. As part of our search to identify dual targeting ligands for these receptors, we have carried out a systematic modification of a selective 5HT7 receptor ligand culminating in the identification of several dual 5-HT1A and 5-HT7 receptor ligands. Compound 16, a butyrophenone derivative of tetrahydroisoquinoline (THIQ), was identified as the most potent agent with low nanomolar binding affinities to both receptors. Interestingly, compound 16 also displayed moderate affinity to other clinically relevant dopamine receptors. Thus, it is anticipated that compound 16 may serve as a lead for further exploitation in our quest to identify new ligands with the potential to treat diseases of CNS origin.

Keywords: Dual receptor ligands, multi-receptor targeting, CNS ligands, serotonin receptors, 5-HT1A receptor and 5-HT7 receptor ligands

Graphical Abstract

An external file that holds a picture, illustration, etc.
Object name is nihms795546u1.jpg

1. Introduction

It is now well established that targeting a single receptor is often inadequate in treating several diseases including diseases originating from the central nervous system. Thus, drugs such as aripiprazole, lurasidone and others derive their superior therapeutic outcomes from their ability to target multiple receptors in the CNS.14

The neurotransmitters, dopamine (DA) and serotonin (5-HT), are of particular interest because of their involvement in several neurological and psychiatric diseases such as schizophrenia, major depressive disorder (MDD), depression, attention deficit and hyperactivity disorder (ADHD), and addiction.58 Recent research has indicated that the serotonin receptors (5-HTRs) in particular play significant roles in CNS physiological activities, and dysregulation of these receptors often results in several diseases. For example, the serotonin 1A receptor (5-HT1AR) which is found predominantly in the dorsal raphe nuclei, hippocampus, and cortico-limbic regions, controls memory, cognition, and mood, functions which are impaired in anxiety, depression and schizophrenia.9 Several lines of evidence now support the anti-negative symptoms and cognitive enhancement effects of ligands which activate 5-HT1AR in schizophrenia.6,10 Similarly, the serotonin 7 receptor (5-HT7R), the most recent addition to the 5-HT receptor subtypes,1113 has been shown to mediate key functions such as sleep, mood, learning, memory, and cognition.1417 Interestingly, the 5-HT7R forms heterodimers with the 5-HT1AR in most brain regions, producing a cross talk which has been implicated in depression and other CNS disorders. Both receptors share over 40% sequence homology which may account for the cross reactivity seen among ligands which interact at both receptors.1820 It stands to reason therefore that agents with dual binding affinities to both receptors may be beneficial as treatment options for depression and other cognitive impairment disorders.

Our lab has been engaged in multiple receptor-targeting in order to extend the scope and utility of CNS agents. The purpose of the current research was to investigate the 1,2,3,4-tetrahydroisoquinoline (THIQ) moiety as a pharmacophore for the dual targeting of the 5-HT1A and 5-HT7 receptors so as to probe their potential utility in CNS diseases. To that end, we have designed and synthesized several arylalkyl substituted THIQs in order to identify new lead agents for further development.

2. Chemistry

In general, the compounds evaluated in this manuscript were obtained by refluxing or carrying out a microwave-assisted reaction of THIQ with various alkylating agents in dimethoxyethane (DME) or acetonitrile (CH3CN) in the presence of K2CO3 as a base and a catalytic amount of KI. The target compounds were prepared by first N-alkylating potassium phthalimide with 1,4-dibromobutane to produce alkyl bromide 1b which was separately reacted with THIQ, decahydroisoquinoline, and isoindoline to afford compounds 1, 2 and 3 respectively (Scheme 1). A three-step reaction procedure was used to synthesize compound 4 (Scheme 2). Commercially available 4-(1H-indol-3-yl)butanoic acid, 2a was reduced using LAH in dry THF to produce the corresponding alcohol which was subsequently converted to the iodo intermediate 2b via an Appel reaction.21,22 The obtained alkylating agent was then coupled to THIQ to afford 4. Deoxygenation of the previously reported indanone 3a23 under Clemmenson reduction conditions yielded 3b which was then used to alkylate THIQ and afforded compound 5 as shown in Scheme 3. Chloride 4a, mesylate 4b, and tosylate 4c were synthesized by literature procedures and subsequently used to alkylate THIQ to yield compounds 6, 7, and 8 respectively (Scheme 4) using the general alkylating conditions described in Scheme 1. Sulfoxide 9 was prepared by oxidation of 8 using the previously reported meta peroxybenzoic acid (m-CPBA) mediated oxidative conditions depicted in Scheme 5.23

Scheme 1
Synthesis of isoindoline-1,3-dione analogs. Reagents and conditions: a) 1,4-dibromobutane, DMF, 100 °C; b) K2CO3/KI, CH3CN, reflux, 12–24 h. I = THIQ; ii = decahydroisoquinoline; iii = isoindoline.
Scheme 2
Synthesis of 3-substituted-1H-indole analog. Reagents and condition: a) LiAlH4 in dry THF, rt,12 h; b) I2/PPh3, imidazole; c) THIQ, K2CO3/KI, DME, reflux,12 h.
Scheme 3
Synthesis of 5-fluoro-2,3-dihydro-1H-indene analog. Reagents and conditions: a) Zn Amalgam, Conc. HCl, toluene, reflux; b) THIQ, K2CO3/KI, DME, reflux, 12 h; c) ethereal HCl.
Scheme 4
Synthesis of 4-fluorobutyrophenone analogs. Reagents and conditions: a) THIQ, K2CO3/KI, DME, MW; b) ethereal HCl.
Scheme 5
Synthesis of sulfoxide analog. Reagents and conditions: a) m-CPBA, MeOH, 0 °C to rt

Alkylating agents 6a, 6b, and 6e were obtained commercially and were used to synthesize compounds 10, 11, and 16 respectively whereas 6c and 6d were prepared following Friedel-Crafts acylation reaction as reported24 and subsequently used to obtain compounds 12a and 14 respectively (Scheme 6). Finally, using potassium ferrocyanide (K4[Fe(CN)6].3H2O) as the cyanide source, palladium catalyzed cyanation25 of 12a afforded compound 12 (Scheme 6). Base-catalyzed hydrolysis of the cyano group26 in 12 afforded the corresponding amide 13 (Scheme 6). Demethylation of 14 with hydrobromic acid afforded compound 15 (Scheme 6).

Scheme 6
Synthesis of 4-subtituted-butyrophenone analogs. Reagents and conditions: a. THIQ, K2CO3/KI, DME, 120 °C, MW; (b) K4[Fe(CN)6].3H2O, Pd(OAc)2, KI, Na2CO3, N 2, DMA, 120 °C, 12 h; (c) KOH, t-butyl alcohol, reflux, 12 h; d) aq. HBr 48%, NaI, ...

3. Results and Discussion

The THIQ moiety has been the subject of several recent publications.2733 In a campaign to synthesize new drugs with selective affinity for the 5-HT7 receptor, we synthesized 2-(4-(3,4-dihydroisoquinolin-2(1H)-yl)butyl)isoindoline-1,3-dione (1) and evaluated its affinity for key 5-HTR subtypes including the 5-HT7R. As shown in Table 1, compound 1 demonstrated a low nanomolar potency at the 5-HT7R and little affinity to the other key 5-HTR subtypes including 5-HT1AR where it is over 50-fold less potent. Replacement of the THIQ ring in 1 with decahydroisoquinoline to yield 2 resulted in close to a 40-fold decrease in binding affinity to the 5-HT7R, with binding affinity at 5-HT1AR and 5-HT2AR remaining essentially unchanged. Compound 2 however, displays selectivity towards the 5-HT2CR (Ki = 37 nM). Further modification of 1 by replacing the tetrahydroisoquinoline ring with isoindoline ring to obtain 3 resulted in significant loss of activity at all receptor subtypes except the 5-HT2CR where there was moderate affinity (Ki = 151 nM). Based on the results of the binding affinities for compounds 1 – 3, it is clear that the THIQ ring serves as an important pharmacophore for binding affinity to the 5-HT7R in these compounds. This observation informed the next design strategy to keep the THIQ group and to focus on modifications elsewhere in the molecule, including that of the isoindoline-1,3-dione moiety.

Table 1
Binding affinity of analogs at selected serotonin receptors

Replacement of the isoindoline-1,3-dione moiety in 3 with indole to obtain 4 restored nanomolar binding affinity to the 5-HT7R, while replacement with 5-fluoro-2,3-dihydro-1H-indene to form 5, led to significant binding affinity to both 5-HT1AR and 5-HT7R (Ki = 193 and 86 nM respectively). Excision of a methylene group from the indene moiety in compound 5 led to ring-opened 6 with improved affinity for both 5-HT1AR and 5-HT7R. Replacement of the benzylic methylene group in 6 with oxygen (7) and sulfur (8) did not result in significant changes. However, oxidation of the sulfide to obtain the sulfoxide 9, increased affinity for both 5-HT1AR (Ki = 41 nM) and 5-HT7R (Ki = 22.5 nM).

Next, the sulfoxide group in 9 was replaced by a carbonyl to form 4-(3,4-dihydroisoquinolin-2(1H)-yl)-1-(4-fluorophenyl)butan-1-one (10) which resulted in a 3-fold increase in binding affinity at the HT1AR (Ki = 12 nM) but a decrease of 16-fold at the 5-HT7R (Ki = 364 nM). Interestingly, affinity at the 5-HT2AR is found to have improved drastically to 14 nM. Similar low nanomolar binding affinities are observed for compounds 11 (the defluorinated analog) and 12 (replacement of the fluoro with the electron withdrawing and hydrophilic cyano substituent) at the 5-HT2AR while significant loss of affinities are noted at the 5-HT1AR and 5-HT7R. However, changing the p-cyano substituent in 12 to the carboxamide 13, the methoxy group 14, or its hydroxy analog 15, produced the desired dual 5-HT1AR and 5-HT7R binding affinity ligands with low nanomolar affinity constants. Thus, it would appear that various substituents covering at least three quadrants of the Craig plot did not yield a clearly defined structure affinity relationship trend. Finally, we evaluated compound 16, with the p-fluoro atom of compound 10 replaced by a chloro atom which yielded the most potent dual 5-HT1AR (Ki = 8.2 nM) and 5-HT7R (Ki = 3.6 nM) binding affinity ligand in the series. Comparing compound 16 and Aripiprazole, both have high affinities at 5-HT1AR (5.6 vrs. 8.2 nM), and 5-HT7R (3.6 vrs. 10.3 nM), but differ significantly at the other serotonin receptors evaluated, with compound 16 having little or no binding at 5-HT2AR and 5-HT2CR (Ki = 2976 nM) and moderate binding at 5-HT2BR (Ki = 232 nM), while Aripiprazole has high affinity for 5-HT2AR (Ki = 8.7 nM) and 5-HT2BR (Ki = 0.36 nM) and moderate affinity to 5-HT2CR (Ki = 76 nM).

The target compounds were also screened at additional CNS receptors with clinical significance including the D2R, D3R, D4R, H1R and SERT and the results reported in Table 2. Compounds 13 showed little if any affinities at the aforementioned receptors/transporter. Compound 4, the indolealkyl substituted analog of 1, produced moderate affinities for D2R, D4R and SERT while the dihydroindene analog 5 had moderate affinities for D3R, D4R and SERT. Opening the dihydroindene ring in 5 with excision of a methylene group (6), or replacing the benzylic carbon with oxygen, sulfur, or sulfoxide (7-9) resulted in significant loss of affinity for SERT with no clear SAR features at the other receptors in Table 2. Replacement of the sulfoxide with a carbonyl (10) produced significant increase in binding at the dopamine receptors, suggesting that perhaps the butyrophenone THIQ scaffold could constitute a useful hit for further development as ligands for multiple receptor targeting. However, probing the electron donating or withdrawing nature and/or the hydrophilic/hydrophobic nature of substituents at the para position of the phenyl ring (10 -16) according to the Craig plot procedure34 did not produce an increase in potency at the dopamine receptors and did not reveal any interesting SAR trend. Regarding their histamine binding affinities, only 10 and 11 have affinity constants below 100 nM suggesting that these compounds may have low propensity for interacting at the histamine H1 receptor and hence less sedative effect.

Table 2
Binding affinity of analogs at dopamine subtype receptors, histamine H1 receptor, and SERT

Of the sixteen compounds reported, three, compounds 13, 14 and 16 (13: Ki = 13 nM, 14: Ki = 38 nM, 16: Ki = 17 nM respectively) show significant binding affinities to the D3R. Given their concentration in limbic and cortical regions of the brain, D3Rs have been hypothesized to be potential targets for the design of new antipsychotics with limited extrapyramidal side effects. However, there have been reports that selective D3R blockade only resulted in marginal antipsychotic effects. This has led to the suggestion and indeed demonstration that dual D2/D3 receptor blockade produce effective antipsychotic actions.3537

The moderate binding affinities of these compounds for the D2 receptors (13: Ki = 218 nM, 14: Ki = 249 nM, 16 Ki = 126 nM), combined with their serotonin binding profiles make them potential drug leads for further exploitation. In particular, the preferential and more potent binding of 16 at D3R (Ki = 17 nM) compared to D2R (7 fold) suggest further evaluation for intrinsic activities and subsequent exploitation in the treatment of CNS conditions including the negative and cognitive symptoms of schizophrenia and bipolar mania.3840 Interestingly, the D3R binding of compound 16 is similar to that of aripiprazole (Ki = 17 vrs. 9.7 nM), while the D2R binding affinity is similar to that of clozapine41 (Ki = 126 nM vrs. pKi = 6.87 or Ki = 130 nM). Strong binding to the D3R may also be associated with procognitive effects, as reported.42

In conclusion, using compound 1 which showed significant selectivity (>50 fold) for 5-HT7 receptor compared to the 5-HT1AR as our starting hit, and guided by results from our SAR studies, we were able to obtain very potent dual 5-HT1A and 5-HT7 receptor affinity ligands. In addition, compound 16 showed moderate binding affinity at D2R, high affinity at D3R, and a 7-fold selectivity for D3R over D2R, which portends a lead with great potential for further development in treating the negative and cognitive symptoms of schizophrenia, as well as bipolar mania. We opine that butyrophenone derivatives of THIQ such as 16 could serve as important leads to exploit for more potent CNS drugs with multi-receptor affinity features.

4. EXPERIMENTAL

Melting points were determined on a Gallenkamp (UK) apparatus and are uncorrected. All NMR spectra were obtained on a Varian 300 MHz Mercury Spectrometer and the free induction decay (FID) data were processed using Mestrelab’s Mnova NMR software (version 8.1) to obtain the reported NMR data. Elemental analyses were carried out by Atlantic Microlab, Inc., Norcross, GA, and are within 0.4% of theory unless otherwise noted. Flash chromatography was performed using CombiFlash® with Davisil grade 634 silica gel. Starting materials were obtained from Sigma–Aldrich and were used without further purification. All microwave assisted syntheses (MW) were carried out using a Biotage Initiator®.

4.1. Synthesis of 2-(4-Bromobutyl)isoindoline-1,3-dione, 1b

A mixture of potassium phthalimide 1a (0.93 g, 5 mmol) and 1,4-dibromobutane (5.4 g, 25 mmol) was stirred in dry DMF (10 mL) at 100 °C for 12 h. The condenser was then set for distillation, and the excess of 1,4-dibromobutane and DMF was removed under reduced pressure. The crude product obtained was purified by column chromatography (silica gel, ethyl acetate/light petroleum 1:50) to afford intermediate 1b as a colorless solid. 1H NMR (CDCl3): δ 7.87-7.84 (2H, m), 7.74-7.71 (2H, m), 3.73 (2H, t, J = 6.9 Hz), 3.45 (2H, t, J = 6.3 Hz), 1.90-1.88 (4H, m).

4.2. General alkylation procedure for compounds 1-3

A mixture of 1b (1 equiv), an appropriate amine (1.2 equiv), KI (100 mg), and K2CO3 (10 equiv), in CH3CN (15 mL) or DME was refluxed for 12–24 h. The reaction progress was monitored by TLC and at completion, the mixture was cooled to room temperature, solvent removed, the resulting residue loaded onto a cartridge and purified by flash chromatography using an EtOAc/hexane gradient up to 80% EtOAc) to give the pure desired products.

4.2.1. 2-(4-(3,4-Dihydroisoquinolin-2(1H)-yl)butyl)isoindoline-1,3-dione, 1

Following the general alkylation procedure described in section 4.2 and using THIQ as the amine, compound 1 was obtained as the free base. Yield: 22%, mp: 68–69 °C. 1H NMR (DMSO-d6): δ 7.86-7.79 (4H, m), 7.07-6.98 (4H, m), 3.58 (2H, t, J = 6.9 Hz), 3.47 (2H, s), 2.75 (2H, t, J = 5.4 Hz), 2.58 (2H, t, J = 6.0 Hz), 2.43 (2H, t, J = 6.9 Hz), 1.68-1.48 (4H, m). Calcd for C21H22N2O2·0.2H2O; C 74.62, H 6.68, N 8.29; Found: C 74.55, H 6.55, N 8.25.

4.2.2. 2-(4-(Octahydroisoquinolin-2(1H)-yl)butyl)isoindoline-1,3-dione, 2

Using decahydroisoquinoline as the amine, compound 2 was prepared similarly to 1 above. Yield: 12%, mp: 64–65°C. 1H NMR (CDCl3): δ 7.84-7.82 (2H, dd, J = 3.0, 8.7 Hz), 7.70 (2H, dd, J = 3.0, 9.0 Hz), 3.70 (2H, t, J = 7.2 Hz), 2.91 (1H, d, J = 8.1 Hz), 2.75 (1H, d, J = 9.0 Hz), 2.31 (2H, s), 1.77 (1H, t, J = 7.2 Hz), 1.71-1.48 (1H, m), 1.26-1.19 (4H, m), 0.98-0.87 (2H, m). Calcd for C21H28N2O2; C 74.08, H 8.29, N 8.23; Found: C; 73.82, H; 8.09, N; 8.19.

4.2.3. 2-(4-(Isoindolin-2-yl)butyl)isoindoline-1,3-dione, 3

Following the general alkylation procedure in section 4.2 and using isoindoline as the amine, compound 3 was obtained as the free base. Yield: 21%, mp: 95–96°C. 1H NMR (DMSO-d6): δ 7.88-7.78 (m, 4H), 7.20-7.12 (m, 4H), 3.76 (s, 4H), 3.59 (t, 2H, J = 5.7 Hz), 2.63 (t, 2H, J = 7.2 Hz), 1.70-1.44 (m, 4H). Calcd for C20H20N2O2·0.11 H2O; C 72.78, H 6.11, N 8.49; Found: C 72.75, H 6.16, N 8.12.

4.3. Synthesis of 3-(4-iodobutyl)-1H-indole, 2b

To a solution of indole-3-butyric acid 2a (2 g, 9.8 mmol) dissolved in dry THF (30 mL) and cooled to 0 °C was added portionwise LiAlH4 (2.2 g, 59 mmol, 6 eq) in dry THF. The mixture was allowed to warm to room temperature (rt) with stirring for 18h. The reaction mixture was cooled to 0 °C and a saturated solution of Na2SO4 (20 mL) was added in a dropwise manner over the period of 30 min. The resulting white precipitate was filtered, the filtrate washed with EtOAc (2 × 100 mL), the pooled organic phase washed with water (50 mL) and saturated brine solution (50 mL), dried over anhydrous Na2SO4 and the solvent removed under reduced pressure to obtain the crude product. The crude 3-(4-hydroxybutyl)-1H-indole was used for the next step without further purification.

The crude obtained was converted to compound 2b following a procedure reported in literature.21 Briefly, to a stirred solution of PPh3 (4.46 g, 17.0 mmol) and imidazole (1.58 g, 17.0 mmol) in DCM (45 mL) at 0 °C, was added I2 (4.32 g, 17.0 mmol) and the reaction mixture was stirred at this temperature for 30 min. Thereafter, a solution of crude 3-(4-hydroxybutyl)-1H-indole (2.30 g, 12.2 mmol) in DCM (5 mL) was added, the reaction mixture was allowed to warm to rt and stirred for 12 h. The crude product was directly purified using silica gel on CombiFlash with gradient up to 40% EtOAc in hexanes to afford compound 2b (2.40 g) as an oily liquid. Yield: 66%. 1H NMR (CDCl3): δ 7.91 (1H, s). 7.59 (1H, d, J = 8.1Hz), 7.35 (1H, d, J = 8.1 Hz), 7.22-/7.17 (1H, t, J = 6.9 Hz), 7.12 (1H, m), 6.97 (1H, d, J = 2.1 Hz), 3.22 (2H, t, J = 6.9 Hz), 2.84 (2H, t, J = 6.9 Hz), 1.96-1.76 (4H, m).

4.4. 2-(4-(1H-indol-3-yl)butyl)-1,2,3,4-tetrahydroisoquinoline, 4

Following the general alkylation procedure described above (section 4.2.) and using the obtained 2b as the alkylating agent, compound 4 was obtained. Yield: 52%, mp: 139–140 °C. 1H NMR (CDCl3): δ 7.96 (1H, s), 7.62-7.60 (1H, d, J = 8.4 Hz), 7.35 (1H, d, J = 7.8 Hz), 7.21-7.15 (1H, m), 7.13-7.07 (4H, m), 7.01-6.98 (2H, m), 2.90 (2H, t, J = 5.7 Hz), 2.81 (2H, t, J = 6.9 Hz), 2.73 (2H, t, J = 6.0 Hz), 2.56 (2H, t, J = 7.2 Hz), 1.80-1.69 (6H, m,). Calcd for C21H24N2; C 82.85, H 7.97, N 9.20; Found: C 82.65, H 7.97, N 8.97.

4.5. Synthesis of 2-(2-chloroethyl)-5-fluoro-2,3-dihydro-1H-indene, 3b

Amalgamated zinc was prepared by stirring a mixture of zinc (1.2 g), HgCl2 (0.12 g) in 5 mL water with conc. HCl (0.1 mL) at room temperature. After stirring for 5 min, the mixture was decanted and followed by adding in order water (1 mL), conc HCl (1.75 mL), toluene (10 mL), and then 2-(2-Chloro-ethyl)-5-fluoro-indan-1-one 3a (2 g, 9.43 mmol), synthesis of which was previously reported by us.23 The mixture was refluxed with stirring for 12 h. The solid was filtered off, aqueous layer was diluted with EtOAc (200 mL), washed with water, and then saturated NaHCO3 (50 mL). The organic layer was dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo followed by column chromatography on silica gel to afford 3b, 1.68 g, Yield 90%. 1H NMR (CDCl3): δ 7.09 (1H, dd, J = 4.8, 7.8 Hz), 6.85 (2H, m), 3.60 (2H, t, J = 7.2 Hz), 3.04 (2H, m), 2.70 (1H, m), 2.56 (2H, m), 1.98 (2H, m).

4.6. 2-(2-(5-Fluoro-2,3-dihydro-1H-inden-2-yl)ethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride, 5

Alkylating agent 3b was reacted with THIQ following the general alkylation procedure described in section 4.2 to obtain compound 5 as its HCl salt. Yield: 42%, mp: 211–212 °C. 1H NMR (DMSO-d6): 10.85 (1H, s), 7.19 (5H, m), 7.02 (1H, d, J = 9.0 Hz), 6.92 (1H, t, J = 9.0 Hz), 4.51 (1H, m), 4.27 (1H, m), 3.67 (1H, m), 3.40 (1H, m), 3.23 (4H, m), 3.02 (4H, m), 2.60 (1H, m), 1.98 (2H, m). Calcd for C20H23ClFN: C 72.00, H 6.95, N 4.20; Found: C 71.89, H 6.97, N 4.28.

4.7. General alkylation procedure for compounds 6-8, 10-12a, 14, and 16

A mixture of alkylating agent (1 equiv), THIQ (1.1 equiv) K2CO3 (1.1 equiv), and KI (catalytic) in DME (10 mL) was placed in a 20 mL microwave vial with a stirrer and tightly sealed. The mixture was subjected to microwave heating at 120°C for 60 mins. The mixture was directly purified on silica by flash chromatography (gradient up to 70% EtOAc in hexanes) to afford compound 7. The free base where necessary, was converted to the HCl salt and crystallized out of a MeOH-Et2O solvent mixture.

4.7.1. 2-(4-(4-Fluorophenyl)butyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride, 6

The synthesis of 1-(4-chlorobutyl)-4-fluorobenzene 4a was previously reported by us23 and following the procedure described in section 4.7., 4a was reacted with THIQ to afford compound 6 as its HCl salt form. Yield: 75%, mp: 205–206 °C. 1H NMR (DMSO-d6): δ 7.30-7.06 (6H, m); 6.99-6.92 (2H, m); 4.60-4.55 (1H, m); 4.01-3.94 (1H, m), 3.65-3.59 (1H, m), 3.51-3.42 (1H, m), 3.27-3.17 (1H, m), 3.07-2.93 (4H, m), 2.66 (2H, t, J = 7.5); 2.08-1.96 (2H, m), 1.75-1.63 (2H, m). Calcd for C19H23ClFN·0.2H2O: C 70.55, H 7.17, N 4.33; Found: C 70.73, H 7.36, N 4.45.

4.7.2. 2-(3-(4-Fluorophenoxy)propyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride, 7

Following the general alkylation procedure described above (section 4.7.), previously reported alkylating agent 3-(4-fluorophenoxy)propyl methanesulfonate 4b23 was reacted with THIQ to give compound 7 as a white crystalline HCl salt. Yield: 30%, mp: 196–197 °C. 1H NMR (DMSO-d6): δ 11.23 (1H, brs), 7.25 (4H, m), 7.15 (2H, m), 6.95 (2H, m), 4,54 (1H, d, J = 15.6 Hz), 4.28 (1H, dd, J = 8.4, 15.6 Hz), 4.06 (2H, t, J = 6.0 Hz), 3.69 (1H, m), 3.24 (2H, m), 3.34 (2H, m), 3.00 (1H, m), 2.28 (2H, m). Calcd for C18H21ClFNO: C 67.18, H 6.58, N 4.35; Found: C 67.10, H 6.55, N 4.38.

4.7.3. 3-((4-Fluorophenyl)thio)propyl 4-methylbenzenesulfonate, 4c

To a solution of 3-(4-fluorophenylthio)propan-1-ol23 (1 g, 5.4 mmol), Et3N (2 mL) in CH2Cl2 (10 mL) was added at room temperature TsCl (1.54 g, 8.1 mmol). The mixture was stirred at room temperature for 12 h, followed by direct purification using column chromatography on silica gel to provide 4c, 1.72 g, Yield 94%. 1H NMR (CDCl3): δ 7.77 (2H, J = 8.4 Hz), 7.34 (2H, J = 8.4 Hz), 7.30 (2H, dd, J = 5.4, 8.4 Hz), 6.97 (2H, J = 8.7 Hz), 4.13 (2H, t, J = 8.0 Hz), 2.86 (2H, J = 7.2 Hz), 1.89 (2H, m).

4.7.4. 2-(3-((4-Fluorophenyl)thio)propyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride, 8

Reacting alkylating agent 4c and THIQ under the general alkylation conditions (section 4.7.) produced compound 8 as an HCl salt. Yield: 29%, mp: 172–173 °C. 1H NMR (DMSO-d6): δ 11.31 (1H, m), 7.44 (2H, m), 7.22 (6H, m), 4.46 (1H, d, J = 15.3 Hz), 4.22 (1H, dd, J = 7.5, 15.3 Hz), 3.61 (1H, m), 3.27 (4H, m), 3.04 (2H, t, J = 6.0 Hz), 2.95 (1H, m), 2.08 (2H, m). Calcd for C18H21ClFNS: C 63.98, H 6.26, N 4.15; Found: C 63.77, H 6.27, N 4.18.

4.7.5. 2-(3-((4-Fluorophenyl)sulfinyl)propyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride, 9

To a solution of 8 (0.2g, 0.59 mmol) in MeOH (5 mL) was added with stirring m-CPBA (0.2 g) at 0 °C. After stirring for 1 h. at room temperature, the mixture was diluted with Et2O (10 mL). A solid precipitate was collected by filtration. Further crystallization from MeOH-Et2O gave 0.15g of 9 as an HCl salt. 73% Yield: 73%, mp: 177–178 °C. 1H NMR (DMSO-d6): δ 10.53 (1H, brs), 7.74 (2H, dd, J = 4.8, 8.4 Hz), 7.45 (2H, t, J = 8.7 Hz), 7.22 (4H, m), 4.50 (1H, d, J = 15.3 Hz), 4.25 (1H, dd, J = 7.5, 15.3 Hz), 3.63 (1H, m), 3.27 (3H, m), 3.14 (2H, m), 3.98 (1H, m), 2.88 (1H, m), 2.15 (1H, m), 2.00 (1H, m). Calcd for C18H21ClFNOS·0.3H2O: C 60.17, H 5.89, N 3.90; Found: C 60.09, H 5.82, H 3.94.

4.7.6. 4-(3,4-Dihydroisoquinolin-2(1H)-yl)-1-(4-fluorophenyl)butan-1-one, 10

Using 4-chloro-1-(4-fluorophenyl)butan-1-one 6a as the alkylating agent, compound 10 was obtained as a white solid (free base) following the general alkylation method (section 4.7.). Yield: 38%, mp: 104–105 °C. 1H NMR (CDCl3): 7.96 (2H, dd, J = 5.4, 9.0 Hz), 6.98–7.11 (6H, m), 3.61 (2H, m), 3.03 (2H, t, J = 7.2 Hz), 2.86 (2H, t, J = 6.0 Hz), 2.72 (2H, t, J = 6.0 Hz), 2.58 (2H, t, J = 6.9 Hz), 2.03 (2H, q, J = 6.9 Hz). Calcd for C19H20FNO: C 76.74, H 6.78, N 4.71; Found: C 76.51, H 6.83, N 4.69.

4.7.7. 4-(3,4-Dihydroisoquinolin-2(1H)-yl)-1-phenylbutan-1-one, 11

Following the general alkylation procedure (section 4.7.), 4-chloro-1-phenylbutan-1-one 6b was reacted with THIQ to produce compound 11 as its HCl salt to afford a white crystalline solid (1.2g). Yield: 69%, mp: 185–187 °C. 1H NMR (DMSO-d6) δ 11.39 (s, 1H), 7.98 (2H, d, J = 7.6 Hz), 7.63 (1H, d, J = 7.3 Hz), 7.53 (2H, dd, J = 7.5 Hz), 7.28 - 7.17 (4H, m), 4.53 (1H, dd, J = 3.1, 15.4 Hz), 4.27 (1H, dd, J = 7.7, 15.6 Hz), 3.68 (1H, s), 3.35 - 3.17 (6H, m), 2.98 (1H, dd, J = 3.3, 12.6 Hz), 2.24 - 2.07 (2H, m). 13C NMR (75 MHz, DMSO-d6) δ 199.18, 136.82, 133.77, 131.96, 129.19, 129.01, 128.95, 128.36, 127.95, 127.09, 127.00, 54.97, 51.91, 48.93, 35.68, 25.19, 18.40. Calcd for C19H22ClNO: C 72.25, H 7.02, N 4.43; Found: C 71.97, H 7.01, N 4.30.

4.7.8. 1-(4-Bromophenyl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)butan-1-one hydrochloride, 12a

Following the procedure in section 4.7., the alkylating agent 1-(4-bromophenyl)-4-chlorobutan-1-one 6c was reacted with THIQ to obtain 12a as its HCl salt. Yield: 54%, mp: 211–212°C. 1H NMR (DMSO-d6) δ 11.44 (1H, s), 7.90 (2H, dd, J = 8.5, 1.9 Hz), 7.73 (2H, dd, J = 8.5, 1.9 Hz), 7.29 - 7.16 (4H, m), 4.51 (1H, d, J = 15.5 Hz), 4.34-4.19 (1H, m), 3.69 - 3.62 (1H, m), 3.36 - 3.19 (6H, m), 2.97 (1H, d, J = 13.1 Hz), 2.13 (2H, q, J = 7.5 Hz). 13C NMR (75 MHz, DMSO-d6) δ 198.43, 135.84, 132.23, 131.96, 130.38, 128.99, 128.93, 127.94, 127.81, 127.07, 126.99, 54.90, 51.90, 48.92, 35.74, 25.17, 18.32. Calcd for C19H21BrClNO: C 57.81, H 5.36, N 3.55; Found: C 57.67, H 5.29, N 3.65.

4.8. 4-(4-(3,4-Dihydroisoquinolin-2(1H)-yl)butanoyl)benzonitrile, 12

To a 25 mL flask equipped with a stirrer was added 12a (0.79 g, 2.6 mmol) in its free base form, dimethylacetamide (DMAC) (15 mL), K4[Fe(CN)6].3H2O (0.93 g, 2.2 mmol), Na2CO3 (0.23 g, 2.2 mmol), KI (73.0 mg, 20 mol%), and Pd(OAc)2 (0.4 mol%). The flask was evacuated and filled with N2 and heated to 120 °C for 12 hours. Reaction conversion was monitored by TLC. Upon completion, the reaction mixture was cooled to rt, 5% NH4OH (20 mL) was added, extracted with 20 mL x 3 of EtOAc, the pooled organic layers was washed with brine (20 mL), dried over Na2SO4 and the filtrate was concentrated in-vacuo. The crude was purified on silica by flash chromatography (Hexanes: EtOAc gradient up to 80% EtOAc) to afford 12 which was converted to the HCl salt (0.508 g) as white crystals. Yield: 68%, mp: 199–200 °C. 1H NMR (DMSO-d6) δ 11.11 (1H, s), 8.12 (2H, dd, J = 1.8, 8.5 Hz), 8.03 (2H, dd, J = 2.1, 8.5 Hz), 7.31-7.16 (4H, m,), 4.55 (1H, dd, J = 3.2, 14.7 Hz), 4.28 (1H, dd, J = 7.7, 15.5 Hz), 3.70 (1H, d, J = 9.7 Hz), 3.36 - 3.21 (6H, m), 3.02 (1H, d, J = 3.6 Hz), 2.15 (2H, q, J = 6.9, 7.9 Hz).13C NMR (75MHz, DMSO-d6) δ 198.70, 140.17, 134.68, 134.28, 132.29, 128.58, 128.38,126.52, 126.13, 125.56, 118.10, 115.77, 57.15, 55.93, 50.81, 36.51, 28.96, 22.03. Calcd for C20H21ClN2O: C 70.48; H 6.21; N 8.22. Found: C 70.30, H 6.36, N 8.15.

4.9. 4-(4-(3,4-Dihydroisoquinolin-2(1H)-yl)butanoyl)benzamide, 13

A mixture of 12 (0.3 g, 1 mmol) and KOH (0.22 g, 4 mmol) in t-BuOH (10 mL) was refluxed for 12 h. The reaction was allowed to cool to room temperature and extracted with EtOAc (15 mLx2). The organic layers were pooled and washed with brine (20 mL), dried over Na2SO4, filtered, and the filtrate reduced in-vacuo. The crude was purified by flash chromatography (Hexanes: EtOAc gradient up to 80% EtOAc) to obtain 13 (0.40 g) as white crystals. Yield: 46%, mp: 177–178°C. 1H NMR (DMSO-d6) δ 8.11 (1H, s), 7.97 (2H, dd, J = 2.5, 8.8 Hz), 7.92 (2H, dd, J = 2.5, 8.8 Hz), 7.54 (1H, s), 7.10 - 6.95 (4H, m), 3.48 (2H, s), 3.06 (2H, t, J = 7.0 Hz), 2.71 (2H, t, J = 5.8 Hz), 2.59 (2H, t, J = 5.8 Hz), 2.48 (2H, t, J = 7.1 Hz), 1.86 (2H, q, J = 7.1 Hz). 13C NMR (75 MHz, DMSO-d6) δ 200.07, 167.50, 139.17, 138.25, 135.30, 134.61, 128.75, 128.17, 128.15, 126.80, 126.28, 125.80, 57.32, 55.86, 50.85, 36.46, 29.06, 21.79. Calcd for C20H22N2O2: C, 74.51; H, 6.88; N, 8.69. Found: C, 74.59; H, 6.70; N, 8.58.

4.10. 4-(3,4-Dihydroisoquinolin-2(1H)-yl)-1-(4-methoxyphenyl)butan-1-one hydrochloride, 14

Following the alkylation procedure described in section 4.7. above and using 4-chloro-1-(4-methoxyphenyl)butan-1-one 6d as the alkylating agent, compound 14 was obtained as the HCl salt. Yield: 60%, mp: 194–195°C. 1H NMR (DMSO-d6) δ 11.57 (1H, s), 7.97 (2H, dd, J = 2.1, 8.8 Hz), 7.31 - 7.19 (4H, m), 7.05 (2H, dd, J = 2.0, 8.7 Hz), 4.53 (1H, d, J = 15.5 Hz), 4.29 (1H, d, J = 11.1 Hz), 3.84 (3H, s), 3.67 (1H, s), 3.35 - 3.11 (6H, m), 2.99 (1H, d, J = 12.7 Hz), 2.16 (2H, q, J = 7.9 Hz,).13CNMR (75 MHz, DMSO-d6) δ 197.55, 163.63, 132.01, 130.69, 129.83, 129.03, 128.94, 127.95, 127.10, 127.00,114.35, 56.04, 55.06, 51.89, 48.89, 35.32, 25.19, 18.56. Calcd for C20H24ClNO2: C 69.45, H 6.99, N 4.05. Found: C 69.28; H 6.87, N 4.09.

4.11. 4-(3,4-Dihydroisoquinolin-2(1H)-yl)-1-(4-hydroxyphenyl)butan-1-one hydrochloride, 15

To a dry microwave vial equipped with a stirrer and charged with NaI (0.17 g, 1.10 mmol) in HBr solution (48% aq., 10 mL) was added compound 14 in its free base form (0.31 g, 1.0 mmol). The mixture was subjected to microwave heating at 110 °C for 30 mins. The reaction vial was allowed to cool to room temperature (rt) and the mixture directly purified using flash column chromatography (gradient elution up to 80% EtOAc in hexane). The product obtained was converted to its HCl salt to obtain compound 15 as a white flaky solid (0.21g). Yield: 63%, mp: 218–219°C. 1H NMR (DMSO-d6) δ 11.13 (1H, s), 10.51 (1H, s), 7.84 (2H, d, J = 8.0 Hz), 7.33 - 7.15 (4H, m), 6.87 (2H, d, J = 7.9 Hz), 4.48 (1H, s), 4.28 (1H, s), 3.66 (1H, s), 3.35 - 2.93 (7H, m), 2.11 (2H, t, J = 7.8 Hz).13C NMR (75 MHz, DMSO-d6) δ 197.24, 162.69, 131.95, 130.85, 128.94, 128.40, 127.98, 127.09, 127.01, 115.69, 55.20, 52.14, 49.06, 35.00, 25.28, 18.74. Calcd. for C19H22ClNO2·0.75H2O; C 66.08, H 6.86, N 4.06; Found: C 66.17, H 6.49, N 4.03.

4.12. 1-(4-Chlorophenyl)-4-(3,4-dihydroisoquinolin-2(1H)-yl)butan-1-one hydrochloride, 16

THIQ was alkylated with 4-chloro-1-(4-chlorophenyl)butan-1-one 6e and the product converted to its HCl salt to afford compound 16 as its HCl salt. Yield: 61%, mp: 209–210 °C. 1H NMR (DMSO-d6): δ 11.00 (brs, 1H), 7.97 (2H, d, J = 9.0 Hz), 7.62 (2H, d, J = 9.0 Hz), 7.27-7.18 (4H, m), 5.4 (1H, d, J = 14.4 Hz), 4.31-4.23 (1H, m), 3.74-3.64 (1H, m), 3.50-3.38 (2H, m), 3.36-3.25 (4H, m), 3.08-2.90 (1H, m), 2.17-2.10 (2H, m). 13C NMR (75 MHz, DMSO-d6): δ 198.25, 138.62, 135.55, 131.96, 130.29, 129.29, 128.97, 128.94, 127.97, 127.08, 127.08, 127.01, 54.93, 51.94, 48.95, 35.75, 25.17, 18.34. Calcd. C19H21Cl2NO; C 65.15, H 6.04, N 4.00; Found: C 65.03, H 6.16, N 3.99.

Receptor Binding studies

Binding affinities reported in Tables 1 and and22 were conducted by the National Institute of Mental Health Psychoactive Drug Screening Program (NIMH-PDSP) unless otherwise stated. Details of the methods and radioligands used for the binding assays were previously reported.3

Acknowledgments

This work would not have been possible without the continuing financial support of the NIH/NIGMS SCORE grant number 2SC1GM08845, RCMI grant number G12 RR 03020 from NIMHD and a Title III Grant to Florida A&M University. The work was also supported in part by the Pharmaceutical Research Center NIH/NCRR 1C06-RR12512-01 Grant. Ki determinations and receptor binding profiles were generously provided by the National Institute of Mental Health’s Psychoactive Drug Screening Program, Contract # HHSN-271-2013-00017-C (NIMH PDSP). The NIMH PDSP is directed by Bryan L. Roth MD, PhD at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscoll at NIMH, Bethesda MD, USA. Funding sources acknowledged had no involvement in the study design, data collection and interpretation, or article preparation and submission of this manuscript.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

References

1. DeLeon A, Patel NC, Crismon ML. Clin Ther. 2004;26:649. [PubMed]
2. Davies MA, Sheffler DJ, Roth BL. CNS Drug Rev. 2004;10:317. [PubMed]
3. Shapiro DA, Renock S, Arrington E, Chiodo LA, Liu LX, Sibley DR, Roth BL, Mailman R. Neuropsychopharmacology. 2003;28:1400. [PubMed]
4. Franklin R, Zorowitz S, Corse AK, Widge AS, Deckersbach T. Neuropsychiatr Dis Treat. 2015;11:2143. [PMC free article] [PubMed]
5. Meltzer HY. Neuropsychopharmacology. 1999;21:106S. [PubMed]
6. Meltzer HY, Li Z, Kaneda Y, Ichikawa J. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27:1159. [PubMed]
7. Volkow ND, Fowler JS, Wang GJ, Swanson JM. Mol Psychiatry. 2004;9:557. [PubMed]
8. Muller CP, Homberg JR. Behav Brain Res. 2015;277:146. [PubMed]
9. Glennon RA, Dukat M, Westkaemper RB. In: Psychopharmacology: The Fourth Generation of Progress: An Official Publication of the American College of Neuropsychopharmacology. Bloom FE, Kupfer DJ, editors. Raven Press; New York: 1995.
10. Newman-Tancredi A, Kleven MS. Psychopharmacology (Berl) 2011;216:451. [PubMed]
11. Ruat M, Traiffort E, Leurs R, Tardivel-Lacombe J, Diaz J, Arrang JM, Schwartz JC. Proc Natl Acad Sci U S A. 1993;90:8547. [PubMed]
12. Lovenberg TW, Baron BM, de Lecea L, Miller JD, Prosser RA, Rea MA, Foye PE, Racke M, Slone AL, Siegel BW, Danielson PE, Sutcliffe JG, Erlander MG. Neuron. 1993;11:449. [PubMed]
13. Bard JA, Zgombick J, Adham N, Vaysse P, Branchek TA, Weinshank RL. J Biol Chem. 1993;268:23422. [PubMed]
14. Leopoldo M, Lacivita E, Berardi F, Perrone R, Hedlund PB. Pharmacol Ther. 2011;129:120. [PMC free article] [PubMed]
15. Hedlund PB, Sutcliffe JG. Trends Pharmacol Sci. 2004;25:481. [PubMed]
16. Matthys A, Haegeman G, Van Craenenbroeck K, Vanhoenacker P. Mol Neurobiol. 2011;43:228. [PubMed]
17. Gasbarri A, Cifariello A, Pompili A, Meneses A. Behav Brain Res. 2008;195:164. [PubMed]
18. Naumenko VS, Popova NK, Lacivita E, Leopoldo M, Ponimaskin EG. CNS Neurosci Ther. 2014;20:582. [PubMed]
19. Hoyer D, Hannon JP, Martin GR. Pharmacol Biochem Behav. 2002;71:533. [PubMed]
20. Renner U, Zeug A, Woehler A, Niebert M, Dityatev A, Dityateva G, Gorinski N, Guseva D, Abdel-Galil D, Frohlich M, Doring F, Wischmeyer E, Richter DW, Neher E, Ponimaskin EG. J Cell Sci. 2012;125:2486. [PubMed]
21. Smith SM, Takacs JM. J Am Chem Soc. 2010;132:1740. [PMC free article] [PubMed]
22. Appel R. Angewandte Chemie International Edition in English. 1975;14:801.
23. Peprah K, Zhu XY, Eyunni SV, Etukala JR, Setola V, Roth BL, Ablordeppey SY. Bioorg Med Chem. 2012;20:1671. [PMC free article] [PubMed]
24. Chowdhury N, Dutta S, Karthick S, Anoop A, Dasgupta S, Pradeep Singh ND. J Photochem Photobiol B. 2012;115:25. [PubMed]
25. Weissman SA, Zewge D, Chen C. J Org Chem. 2005;70:1508. [PubMed]
26. Hall JH, Gisler M. J Org Chem. 1976;41:3769.
27. Silvano E, Millan MJ, Mannoury la Cour C, Han Y, Duan L, Griffin SA, Luedtke RR, Aloisi G, Rossi M, Zazzeroni F, Javitch JA, Maggio R. Mol Pharmacol. 2010;78:925. [PubMed]
28. Liu S, Zha C, Nacro K, Hu M, Cui W, Yang YL, Bhatt U, Sambandam A, Isherwood M, Yet L, Herr MT, Ebeltoft S, Hassler C, Fleming L, Pechulis AD, Payen-Fornicola A, Holman N, Milanowski D, Cotterill I, Mozhaev V, Khmelnitsky Y, Guzzo PR, Sargent BJ, Molino BF, Olson R, King D, Lelas S, Li YW, Johnson K, Molski T, Orie A, Ng A, Haskell R, Clarke W, Bertekap R, O’Connell J, Lodge N, Sinz M, Adams S, Zaczek R, Macor JE. ACS Med Chem Lett. 2014;5:760. [PMC free article] [PubMed]
29. Wasik A, Romanska I, Michaluk J, Kajta M, Antkiewicz-Michaluk L. Neurotox Res. 2014;26:240. [PMC free article] [PubMed]
30. Canale V, Guzik P, Kurczab R, Verdie P, Satala G, Kubica B, Pawlowski M, Martinez J, Subra G, Bojarski AJ, Zajdel P. Eur J Med Chem. 2014;78:10. [PubMed]
31. Mozdzen E, Papp M, Gruca P, Wasik A, Romanska I, Michaluk J, Antkiewicz-Michaluk L. Eur J Pharmacol. 2014;729:107. [PubMed]
32. Zajdel P, Marciniec K, Maslankiewicz A, Paluchowska MH, Satala G, Partyka A, Jastrzebska-Wiesek M, Wrobel D, Wesolowska A, Duszynska B, Bojarski AJ, Pawlowski M. Bioorg Med Chem. 2011;19:6750. [PubMed]
33. Vermeulen ES, van Smeden M, Schmidt AW, Sprouse JS, Wikstrom HV, Grol CJ. J Med Chem. 2004;47:5451. [PubMed]
34. Craig PN. In: The Basis of Medicinal Chemistry. Wolff ME, editor. Wiley-Interscience; New York: 1980. pp. 331–348.
35. Depoortere R, Bardin L, Auclair AL, Kleven MS, Prinssen E, Colpaert F, Vacher B, Newman-Tancredi A. Br J Pharmacol. 2007;151:253. [PMC free article] [PubMed]
36. Butini S, Gemma S, Campiani G, Franceschini S, Trotta F, Borriello M, Ceres N, Ros S, Coccone SS, Bernetti M, De Angelis M, Brindisi M, Nacci V, Fiorini I, Novellino E, Cagnotto A, Mennini T, Sandager-Nielsen K, Andreasen JT, Scheel-Kruger J, Mikkelsen JD, Fattorusso C. J Med Chem. 2009;52:151. [PubMed]
37. Dutta AK, Venkataraman SK, Fei XS, Kolhatkar R, Zhang S, Reith ME. Bioorg Med Chem. 2004;12:4361. [PubMed]
38. Agai-Csongor E, Domany G, Nogradi K, Galambos J, Vago I, Keseru GM, Greiner I, Laszlovszky I, Gere A, Schmidt E, Kiss B, Vastag M, Tihanyi K, Saghy K, Laszy J, Gyertyan I, Zajer-Balazs M, Gemesi L, Kapas M, Szombathelyi Z. Bioorg Med Chem Lett. 2012;22:3437. [PubMed]
39. Neill JC, Grayson B, Kiss B, Gyertyan I, Ferguson P, Adham N. Eur Neuropsychopharmacol. 2016;26:3. [PubMed]
40. Adham N, Gyertyan I, Kiss B. Eur Neuropsychopharmacol. 2014;24:S233.
41. Lyles-Eggleston M, Altundas R, Xia J, Sikazwe DMN, Fan P, Yang Q, Li S, Zhang W, Zhu X, Schmidt AW, Vanase-Frawley M, Shrihkande A, Villalobos A, Borne RF, Ablordeppey SY. J Med Chem. 2004;47:497. [PubMed]
42. Zimnisky R, Chang G, Gyertyan I, Kiss B, Adham N, Schmauss C. Psychopharmacology (Berl) 2013;226:91. [PMC free article] [PubMed]