Multitarget 1,4-Dioxane Compounds Combining Favorable D₂-like and 5-HT_1A Receptor Interactions with Potential for the Treatment of Parkinson’s Disease or Schizophrenia

Abstract

The effect of methoxy and hydroxy substitutions in different positions of the phenoxy moiety of the N-((6,6-diphenyl-1,4-dioxan-2-yl)methyl)-2-phenoxyethan-1-amine scaffold on the affinity/activity for D₂-like, 5-HT_1A and α₁-adrenoceptor subtypes was evaluated. Multitarget compounds with suitable combinations of dopaminergic and serotoninergic profiles were discovered. In particular, the 2-methoxy derivative 3 showed a multitarget combination of 5-HT_1A/D₄ agonism and D₂/D₃/5-HT_2A antagonism, which may be a favorable profile for the treatment of schizophrenia. Interestingly, the 3-hydroxy derivative 8 behaved as a partial agonist at D₂ and as a potent full agonist at D₃ and D₄ subtypes. In addition to its potent 5-HT_1A receptor agonism, such a dopaminergic profile makes 8 a potential multitarget compound for the treatment of Parkinson’s disease (PD). Indeed, the activation of 5-HT_1A receptors might be helpful in reducing dyskinetic side effects associated with dopaminergic stimulation.

Graphical Abstract

The multitarget or “magic shotgun” approach to drug discovery has been raised with an increasing interest and awareness within the medicinal chemistry community, owing to its advantages in the treatment of complex diseases.¹ Although in some cases combined therapies are used, multitarget drugs may offer clear advantages, including more predictive pharmacokinetics, better patient compliance, and reduced risk of drug interactions.^2,3

Several neurotransmitter pathways are functionally altered in complex diseases, such as psychiatric and neurodegenerative disorders.⁴ Among them, central dopamine (DA) and serotonin (5-HT) receptor systems play crucial roles in regulating psycho-emotional, cognitive and motor functions in the central nervous system (CNS). In the DA receptor system, D₂-like receptors, comprising D₂, D₃, and D₄ subtypes, are involved in several pathological conditions in the CNS and thus are considered attractive drug targets.⁵ In particular, full or partial D₂ and D₃ receptor agonists are widely used in Parkinson’s disease (PD) therapy, whereas D₂/D₃ receptor antagonists or partial agonists proved to be efficacious in the treatment of schizophrenia. Noteworthy, different DA disorders might be treated with D₂/D₃ partial agonists with different levels of intrinsic activity. In particular, D₂/D₃ partial agonists endowed with higher intrinsic activity are efficacious in case of DA activity deficiency (e.g. PD), while for “DA hyperactivation” diseases (e.g. schizophrenia) lower intrinsic activity D₂/D₃ partial agonists are preferred.^5–8

Moreover, D₄ receptor agonists may be useful in reversing cognitive deficits in schizophrenia.⁹ Early reports indicated that D₄ antagonists might be potential therapeutic agents for attenuating L-DOPA-induced dyskinesias.¹⁰ Additional data also highlight the therapeutic benefit of molecules targeting the 5-HT_lA receptor in treating schizophrenia and PD.¹¹

The multitarget approach, combining DA and 5-HT receptor systems, revealed improved results in the treatment of polyfactorial pathologies such as PD and schizophrenia.^12,13 In particular, the combination of 5-HT_1A receptor agonism, D₂/D₃ antagonism and 5-HT_2A antagonism has been reported to be beneficial in the treatment of schizophrenia.^14,15 5-HT_1A receptor agonists may also behave as adjuvants in ameliorating the induction of dyskinesia in L-DOPA-treated PD patients.^16,17 SLV-308 (pardoprunox), a multitarget agent in which a full 5-HT_1A receptor agonism is associated with a partial D₂/D₃ receptor agonism (Figure 1), reached phase III clinical trials for the treatment of PD. Compared with other dopaminergic agents, SLV-308 has lower propensity to elicit side effects like dyskinesia.¹⁸ Therefore, ligands endowed with such a multitarget profile might be effective in PD pharmacotherapy.

Figure 1.

Chemical structure and biological profile of SLV-308 (pardoprunox).¹⁸

WB-4101 (1, Figure 2), a well-known α₁-adrenoceptor (α₁-AR) antagonist, has been the starting point of numerous SAR studies previously reported by us. This compound also shows good affinity for 5-HT_1A receptors (pK_i = 8.61) and moderate affinity for D₂-like receptors (pK_i = 6.91).¹⁹ This compound includes two phenoxyethylamine fragments, which might play a role in determining its affinity for DA receptors. In fact, this fragment is part of the chemical structures of several ligands endowed with DA receptor affinity.^20–22 Extensive structure-activity relationship (SAR) studies described for adrenergic and serotoninergic receptors demonstrated that the replacement of the 1,4-benzodioxane nucleus of 1 with the 6,6-diphenyl-1,4-dioxane scaffold, affording compound 2, significantly decreased the affinity for α₁-AR subtypes, while maintaining high affinity for 5-HT_1A receptor (Table 1).²³ The removal of one or both of the ortho methoxy groups of 2 led to compounds 3 and 4, respectively, which behaved as potent 5-HT_1A receptor and α₁-AR ligands with high selectivity for α_1d over α_1a and α_1b subtypes.²³ Recently, compound 3 and its 2-hydroxy and 2-(methoxymethoxy) analogues 5 and 6 (Figure 2), all endowed with nanomolar 5-HT_1A receptor affinity, were evaluated at D₂-like receptor subtypes. Among them, 5 and especially 3 displayed good affinity for all the D₂-like receptor subtypes (Table 1).²⁴

Figure 2.

Chemical structures of compounds 1–13. The phenoxyethylamine fragments are in bold.

Table 1.

Affinity constants (pK_i) of 2-13for human recombinant D₂, D₃ and D₄ receptors, α_1a-, α_1b-, α_1d-AR subtypes, and 5-HT_1A receptor^a

compd	R	pKi, human cloned receptor
		D2	D3	D4	α1a	α1b	α1d	5-HT1A
2	2,6-OCH3	6.33	6.34	5.77	6.47b	6.49b	7.18b	8.85b
3	2-OCH3	7.91c	7.88c	8.08c	7.56b	7.25b	8.94b	9.18b
4	H	7.26	7.92	6.80c	6.77b	6.92b	8.44b	9.23b
5	2-OH	7.81c	7.47c	7.44c	6.71c	6.43c	7.11c	9.16c
6	2-OCH2OCH3	6.98c	7.18c	7.29c	6.55c	6.54c	7.10c	9.20c
7	3-OCH3	6.88	7.37	6.45	6.41	<6	6.98	8.91
8	3-OH	8.50	8.86	7.98	<6	<6	6.56	8.94
9	4-OCH3	5.85	6.41	6.45	<6	<6	<6	7.17
10	4-OH	6.70	7.37	6.49	6.56	<6	7.01	7.59
11	2,3-OCH3	6.69	6.79	6.87	NDb	NDb	NDb	NDb
12	3,4-OCH3	<5	6.10	5.84	<6	<6	<6	7.71
13	3,4-OCH2O-	6.70	6.99	6.79	6.32	<6	6.81	8.04

^aAffinity values are reported as pK_i = -logK_i. Equilibrium dissociation constants (K_i) were derived from IC₅₀ values using the Cheng-Prusoff equation.³³ Each experiment was performed in triplicate. K_i values were from three experiments, which agreed within ± 20%.

^bTaken from reference 23.

^cTaken from reference 24.

^dND = not determined.

Altogether, the results obtained so far have demonstrated that small changes of the substituents on the phenoxy terminal of this class of compounds differentially affect the affinity profiles at D₂-like, 5-HT_1A and α₁-AR subtypes. On the basis of this observation and encouraged by the interesting 5-HT_1A/D₂-like receptor affinity profiles of the 2-methoxy and the 2-hydroxy derivatives 3 and 5, respectively, the aim of the present study was to obtain novel multitarget analogues with improved D₂-like receptor affinity, high affinity for 5-HT_1A, and low affinity for α₁-AR subtypes. As mentioned above, this multitarget affinity profile might be favorable in schizophrenia or PD pharmacotherapy, depending on the combination of functional potencies and efficacies.

To pursue this aim, the effect of the substituent in different positions of the phenoxy terminal was explored by moving the methoxy or hydroxy groups of the known compounds 3 and 5, respectively, from ortho to meta and para positions, affording the novel compounds 7-10 (Figure 2). Moreover, the high 5-HT_1A receptor affinity and selectivity over α₁-AR shown by the previously reported 2,6-dimethoxy derivative 2 prompted us to evaluate this compound for its affinity at D₂-like receptor subtypes and to investigate the effect of di-substitution in different positions on the phenoxy moiety, by studying the novel compounds 11-13 (Figure 2).

The novel compounds 7-13 were tested at human D₂, D₃, D₄, 5-HT_1A receptors and α₁-AR subtypes, in radioligand competition binding assays. The previously reported compound 4 was also tested for its affinity at D₂-like receptor subtypes, to evaluate the effect of removal of substituents in the phenoxy moiety. Finally, the pharmacological profile of the most interesting compounds 3 and 8 was further assessed in binding assays at other selected targets and in in vitro functional assays at receptors in which they showed the highest affinities.

RESULTS AND DISCUSSION

The novel compounds were prepared following the procedure described in Scheme 1. The suitable amines 14–20, commercially available or prepared according to previously reported procedures,^25–27 were reacted with the iodo derivative 21²³ or the tosyl derivative 22²⁸ in 2-methoxyethanol, to give the final compounds 7, 9, 11-13, and the intermediates 23 and 24. The 3- and 4-hydroxy derivatives 8 and 10, respectively, were prepared by cleavage of the benzyl group of 23 and 24 with 4% formic acid in methanol in the presence of 10% palladium on activated charcoal as a catalyst.

Scheme 1 –

a) CH₃OCH₂CH₂OH, reflux, 5 h; b) HCOOH/MeOH, Pd/C, 24 h.

The pharmacological profiles of 7–13 were evaluated by radioligand competition binding assays using the radioligands [³H]N-methylspiperone to label hD₂, hD₃ or hD₄ receptors stably expressed in HEK293 cells, [³H]Prazosin to label cloned human α₁-ARs expressed in CHO cells and [³H]8-OH-DPAT to label cloned human 5-HT_1A receptors expressed in HeLa cells, according to previously reported procedures.^29–32 The previously reported compounds 2 and 4 were also evaluated at hD₂, hD₃, and hD₄ subtypes. The affinity values, expressed as pK_i, were calculated according to the Cheng–Prusoff equation³³ and are reported in Table 1 together with those of 3, 5, and 6, included for useful comparison. For the most interesting compounds 3 and 8 the affinity values, expressed as pK_i, were also determined by receptor binding assays at other targets, using [³H]SCH23390 to label human D₁ receptors stably expressed in mouse fibroblast cells, and I¹²⁵DOI to label human 5-HT_2A and 5-HT_2C receptors stably expressed in HEK cells (data were obtained through the NIDA Addiction Treatment Discovery Program contract with Oregon Health & Science University).

From an analysis of the data reported in Table 1 it can be observed that all the novel compounds 7-13 show low affinity for α₁-AR subtypes (all pK_i values ≤ 7.01). The unsubstituted compound 4 binds D₂-like receptor subtypes and shows a modest preference for the D₃ subtype (D₃/D₄ = 13.4, D₃/D₂ = 4.6). Concerning the methoxy-substituted derivatives, the shifting of the methoxy group of 3 from the 2- to 3-position of the phenoxy terminal, affording compound 7, causes a significant decrease in the affinity for all the studied targets with the exception of 5-HT_1A receptor (pK_i = 8.91). Therefore, unlike the lead 3, its isomer 7 proved to be highly selective for the 5-HT_1A receptor over α₁-AR and D₂-like subtypes. Instead, the presence of the methoxy substituent in the 4-position (compound 9) is detrimental for the affinity for all studied receptors. The insertion of a second methoxy group in the 6-position of the phenoxy moiety of 3 (compound 2) reduced the affinities for D₂, D₃ and D₄ receptors. Therefore, this compound proved to be highly selective for the 5-HT_1A receptor not only over α₁-ARs,²³ but also over the D₂-like receptor subtypes. All the other di-substituted derivatives (11-13) show decreased affinities for all the targets compared to the mono-methoxy lead 3.

Concerning the hydroxy-substituted compounds, analogously to what was observed for the methoxy derivatives, no favorable effect on the affinities for all the studied targets was observed when the hydroxy group is in the para position (compound 10), leading us to hypothesize that the steric bulk in this position is detrimental for the interaction with such receptor systems. Compared to the 2-hydroxy derivative 5, the 3-hydroxy isomer 8 maintains high affinity for the 5-HT_1A receptor and low affinity for α₁-ARs. Interestingly, compound 8 also shows significantly increased affinities for D₂, D₃, and D₄ receptors.

Overall, among the mono-substituted derivatives, the methoxy in 2-position favors a good 5-HT_1A/D₂-like affinity profile combination, but also confers to compound 3 high affinity for α_1d-AR. A more optimally balanced 5-HT_1A/D₂-like multitarget profile is seen with the 3-hydroxy derivative 8, which also binds all the α₁-AR subtypes with very low affinity (all pK_i values ≤ 6.56).

Due to their interesting multitarget 5-HT_1A/D₂-like affinity profiles, compounds 3 and 8 were also evaluated by binding assays at other selected targets (D₁, 5-HT_2A, and 5-HT_2C receptors - data were obtained through the NIDA Addiction Treatment Discovery Program contract with Oregon Health & Science University). The results reveal that compound 8 shows affinity values for all the studied targets (pK_i: D₁ = 6.91, 5-HT_2A = 5.85, 5-HT_2C = 5.01) lower than those of compound 3 (pK_i: D₁ = 7.64, 5-HT_2A = 7.28, 5-HT_2C = 5.74) and has, therefore, the best multitarget 5-HT_1A/D₂-like selectivity profile within this series of compounds.

Compounds 3 and 8 were also evaluated in in vitro functional assays at all receptors for which they had pK_i values > 6. The results, reported in Table 2, show that derivative 3 behaves as an antagonist with very low potency at the D₁ receptor and with higher potencies at D₂ and D₃ subtypes. On the contrary, it is a potent full agonist at the D₄ receptor. Concerning the serotoninergic system, its previously reported high 5-HT_1A agonist potency²³ is associated with a weak antagonism at the 5-HT_2A subtype. Considering that the combination of 5-HT_1A receptor agonism, D₂/D₃ antagonism and 5-HT_2A antagonism has been reported to be beneficial in the treatment of schizophrenia,^14,15 and that D₄ receptor stimulation might improve cognitive impairment associated with schizophrenia,⁹ the multitarget pharmacological profile of 3 might be advantageous in the treatment of such a disorder.

Table 2.

Potency Values (Expressed as pEC₅₀^a or pIC₅₀^a) and Efficacy Values (Expressed as % stimulation^b or % inhibition^c) of Compounds 3and 8at Dopamine D₁-D₄, 5-HT_1A, and 5-HT_2A receptors.

Receptor	Functional profile of 3		Functional profile of 8
	pEC50 (pIC50)	% stimulationb (% inhibition)c	pEC50 (pIC50)	% stimulationb (% inhibition)c
D1 cAMP assay	(5.90 ± 0.04)	(91.3)	(5.49 ± 0.10)	(78)
D2 mitogenesis assay	(7.60 ± 0.10)	(95.0)	7.49 ± 0.11	65.8
D3 mitogenesis assay	(6.72 ± 0.07)	(88.0)	8.99 ± 0.09	101.7
D4 adenylate cyclase	8.84 ± 0.12	89.6	8.80 ± 0.07	96.2
5-HT1A [35S]GTPγS binding	9.40 ± 0.13d	81.5d	8.28 ± 0.15	86.4
5-HT2A IP-1 formation	(5.85 ± 0.06)	(96.5)	NDe	NDe

^aEach experiment was performed in triplicate. pEC₅₀ or pIC₅₀ values were from three experiments and data are presented as means ± SEM.

^b% Stimulation was determined in comparison to standard agonists SKF-38393 (D₁), quinpirole (D₂, D₃, D₄), serotonin (5-HT_1A, 5-HT_2A).

^c% Inhibition was determined in comparison to standard antagonists SCH 23390 (D₁), (+)-butaclamol (D₂, D₃), NGB 2904 (D₃) and haloperidol (D₄), WAY 100,635 (5-HT_1A), Ketanserin (5-HT_2A). Data were obtained through the NIDA Addiction Treatment Discovery Program contract with Oregon Health & Science University.

^dTaken from reference 23.

^eND = not determined.

The 3-hydroxy derivative 8 behaves as a very weak antagonist at D₁, as a partial agonist at D₂ and as a potent full agonist at D₃ and D₄ subtypes. Moreover, it shows a potent 5-HT_1A receptor agonism, that might be helpful in reducing dyskinetic side effects associated with dopaminergic stimulation. The multitarget profile of 8 makes this compound a potential therapeutic agent for the treatment of PD.

In conclusion, we investigated how methoxy and hydroxy groups in different positions on the phenoxy moiety of 4 may afford multitarget compounds with suitable combinations of dopaminergic and serotoninergic affinity/activity profiles.

The 2-methoxy derivative 3 and the 3-hydroxy derivative 8, endowed with good affinity for D₂-like and 5-HT_1A receptors, emerged as the most interesting compounds in the series. The multitarget combination of 5-HT_1A/D₄ agonism and D₂/D₃/5-HT_2A antagonism makes 3 a good starting point to develop new pharmacological tools potentially useful in the treatment of schizophrenia. Due to its simultaneous agonist potency at D₂-like subtypes and the 5-HT_1A receptor, derivative 8 might be useful in PD therapy. Indeed, the activation of 5-HT_1A receptors might be helpful in reducing dyskinetic side effects associated with dopaminergic stimulation. Looking to the future, evaluation of 3 and 8 in schizophrenia or PD animal models would shed light on their therapeutic potential.

Methods

Chemistry

General

Melting points were taken in glass capillary tubes on a Büchi SMP-20 apparatus and are uncorrected. IR and NMR spectra were recorded on Perkin-Elmer 297 and Varian Mercury AS400 instruments, respectively. Chemical shifts are reported in parts per million (ppm) relative to tetramethylsilane (TMS), and spin multiplicities are given as s (singlet), d (doublet), dd (double doublet), t (triplet), or m (multiplet). IR spectral data (not shown because of the lack of unusual features) were obtained for all compounds reported and are consistent with the assigned structures. The microanalyses were recorded on FLASH 2000 instrument (ThermoFisher Scientific). The elemental composition of the compounds agreed to within ± 0.4% of the calculated value. Chromatographic separations were performed on silica gel columns (Kieselgel 40, 0.040–0.063 mm, Merck) by flash chromatography. Compounds were named following IUPAC rules as applied by ChemBioDraw Ultra (version 11.0) software for systematically naming organic chemicals.

N-((6,6-Diphenyl-1,4-dioxan-2-yl)methyl)-2-(3-methoxyphenoxy)ethanamine (7).

A solution of 14 (Aldrich, 1.61 g, 10.5 mmol) and 21²³ (1.33 g, 3.5 mmol) in 2-methoxyethanol (20 mL) was heated to reflux for 5 h. Removal of the solvent under reduced pressure gave a residue, which was dissolved in water. The aqueous solution was basified with NaOH and extracted with CHCl₃. Removal of dried solvents gave a residue, which was purified by column chromatography, eluting with cyclohexane/ethyl acetate 1:1, to give 7 as an oil: 26% yield. The free base was transformed into the hydrochloride salt, which was recrystallized from 2-PrOH: mp 63–68 °C. ¹H-NMR (400 MHz, CDCl₃) δ: 10.59 (br s, 1H, exchangeable with D₂O), 8.85 (br s, 1H, exchangeable with D₂O), 7.58–7.09 (m, 11H), 6.47 (m, 3H), 4.58 (d, 1H), 4.35 (m, 2H), 4.01 (m, 1H), 3.80 (m, 1H), 3.68 (s, 3H), 3.65–3.08 (m, 6H). Anal. calcd for C₂₆H₂₉NO₄·HCl·H₂O: C, 65.88%, H, 6.80%, N, 2.96%. Found: C, 65.85%, H, 6.62%, N, 2.90%.

3-(2-(((6,6-Diphenyl-1,4-dioxan-2-yl)methyl)amino)ethoxy)phenol (8).

A solution of 23 (1.22 g, 2.47 mmol) in 4.4% HCOOH/MeOH (35 mL) was added dropwise to a mixture of 10% Pd/C (1.80 g) in 4.4% HCOOH/MeOH (70 mL). The mixture was stirred overnight at room temperature under nitrogen atmosphere. After the catalyst was filtered off over Celite and washed with MeOH, the solvent was evaporated and the residue was dissolved in 3 M HCl solution in MeOH and stirred for 30 min. After evaporation of the solvent, the residue was recrystallized from 2-PrOH: 91% yield; mp 165–167 °C. ¹H-NMR (400 MHz, DMSO) δ: 9.58 (br s, 2H, exchangeable with D₂O), 9.22 (br s, 1H, exchangeable with D₂O), 7.58 (d, 2H), 7.40–7.01 (m, 9H), 6.40 (m, 3H), 4.84 (d, 1H), 4.37 (m, 1H), 4.22 (m, 2H), 3.99–3.72 (m, 5H), 3.17 (m, 1H), 2.83 (dd, 1H). Anal. calcd for C₂₅H₂₇NO₄·HCl·2H₂O: C, 62.82%, H, 6.75%, N, 2.93%. Found: C, 62.69%, H, 6.81%, N, 2.88%.

4.1.4. N-((6,6-Diphenyl-1,4-dioxan-2-yl)methyl)-2-(4-methoxyphenoxy)ethanamine (9).

This compound was prepared starting from 16 (Aldrich) and 22²⁸ following the procedure described for 7. An oil was obtained: 28% yield. The free base was transformed into the hydrochloride salt, which was recrystallized from 2-PrOH: mp 156–158 °C. ¹H-NMR (400 MHz, CDCl₃) δ: 8.93 (br s, 2H, exchangeable with D₂O), 7.50 (d, 2H), 7.28 (m, 8H), 6.78 (dd, 4H), 4.58 (d, 1H), 4.32 (m, 2H), 4.01 (m, 1H), 3.80 (dd, 1H), 3.72 (s, 3H), 3.60 (d, 1H), 3.45 (dd, 1H), 3.35 (m, 2H), 3.19 (m, 2H). Anal. calcd for C₂₆H₂₉NO₄·HCl: C, 68.49%, H, 6.63%, N, 3.07%. Found: C, 68.57%, H, 6.50%, N, 3.00%.

4-(2-((6,6-Diphenyl-1,4-dioxan-2-yl)methylamino)ethyl)phenol (10).

This compound was prepared starting from 24 following the procedure described for 8. The residue was recrystallized from 2-PrOH: 27% yield; mp 192–194 °C. ¹H-NMR (400 MHz, DMSO) δ: 9.10 (br s, 2H, exchangeable with D₂O), 9.02 (br s, 1H, exchangeable with D₂O), 7.59 (d, 2H), 7.42–7.18 (m, 8H), 6.84 (d, 2H), 6.68 (d, 2H), 4.83 (d, 1H), 4.19 (m, 2H), 3.90 (m, 1H), 3.78 (dd, 1H), 3.52–3.22 (m, 4H), 3.17 (m, 2H). Anal. calcd for C₂₅H₂₇NO₄·HCl·2H₂O: C, 62.82%, H, 6.75%, N, 2.93%. Found: C, 62.99%, H, 6.80%, N, 2.98%.

2-(2,3-Dimethoxyphenoxy)-N-((6,6-diphenyl-1,4-dioxan-2-yl)methyl)ethanamine (11).

This compound was prepared starting from 18²⁵ and 22²⁸ following the procedure described for 7. An oil was obtained: 33% yield. ¹H-NMR (400 MHz, CDCl₃) δ: 7.53 (d, 2H), 7.41–7.19 (m, 8H), 6.99 (t, 1H), 6.62 (dd, 2H), 4.63 (d, 1H), 4.17 (m, 2H); 3.93–3.73 (m, 8H), 3.66–3.50 (m, 2H), 3.14–2.72 (m, 4H), 1.85 (br s, 1H, exchangeable with D₂O). Anal. calcd for C₂₆H₂₉NO₄·HCl: C, 68.49%, H, 6.63%, N, 3.07%. Found: C, 68.57%, H, 6.50%, N, 3.00%. The free base was transformed into the oxalate salt, which was recrystallized from 2-PrOH: mp 179–181 °C, Anal. calcd for C₂₇H₃₁NO₅·H₂C₂O₄: C, 64.55%, H, 6.16%, N, 2.60%. Found: C, 64.50%, H, 6.29%, N, 2.72%.

2-(3,4-Dimethoxyphenoxy)-N-((6,6-diphenyl-1,4-dioxan-2-yl)methyl)ethanamine (12).

This compound was prepared starting from 19²⁵ and 21²³ following the procedure described for 7. An oil was obtained: 76% yield. The free base was transformed into the hydrochloride salt, which was recrystallized from 2-PrOH: mp 75–80 °C. ¹H-NMR (400 MHz, DMSO) δ: 9.35 (br s, 1H, exchangeable with D₂O), 8.26 (br s, 1H, exchangeable with D₂O), 7.55 (d, 1H), 7.41–7-14 (t, 9H), 6.84 (d, 1H), 6.60 (s, 1H), 6.49 (dd, 1H), 4.84 (d, 1H), 4.39 (m, 2H), 3.91 (m, 1H), 3.81 (m, 1H), 3.70 (s, 3H), 3.68 (s, 3H), 3.53–3.05 (m, 6H). Anal. calcd for C₂₇H₃₁NO₅·HCl: C, 66.73%, H, 6.64%, N, 2.88%. Found: C, 66.87%, H, 6.51%, N, 2.78%.

2-(Benzo[d][1,3]dioxol-5-yloxy)-N-((6,6-diphenyl-1,4-dioxan-2-yl)methyl)ethanamine (13).

This compound was prepared starting from 20 (Aldrich) and 21²³ following the procedure described for 7. An oil was obtained: 72% yield. The free base was transformed into the hydrochloride salt, which was recrystallized from 2-PrOH: mp 142–146 °C. ¹H-NMR (400 MHz, CDCl₃) δ: 7.55 (d, 1H), 7.41–7-14 (m, 9H), 6.70 (d, 1H), 6.52 (s, 1H), 6.35 (dd, 1H), 5.90 (s, 2H), 4.61 (d, 1H), 4.02 (m, 2H), 3.82 (m, 1H), 3.78 (m, 1H), 3.52 (m, 2H), 3.05–2.82 (m, 3H), 2.72 (dd, 1H), 2.48 (br s, 1H, exchangeable with D₂O). Anal. calcd for C₂₆H₂₇NO₅·HCl: C, 66.45%, H, 6.01%, N, 2.98%. Found: C, 66.33%, H, 5.90%, N, 2.92%.

2-(3-(Benzyloxy)phenoxy)-N-((6,6-diphenyl-1,4-dioxan-2-yl)methyl)ethanamine (23).

This compound was prepared starting from 15²⁶ and 22²⁸ following the procedure described for 7. An oil was obtained: 57% yield. ¹H-NMR (400 MHz, CDCl₃) δ:7.55 (d, 2H), 7.47–7.15 (m, 14H), 6.58 (m, 3H), 5.02 (s, 1H), 4.62 (d, 1H), 4.05 (m, 2H), 3.83 (m, 1H), 3.79 (m, 1H), 3.58 (m, 2H), 2.90 (m, 3H), 2.72 (dd, 1H), 2.27 (br s, 1H, exchangeable with D₂O).

2-(4-(Benzyloxy)phenoxy)-N-((6,6-diphenyl-1,4-dioxan-2-yl)methyl)ethanamine (24).

This compound was prepared starting from 17²⁷ and 22²⁸ following the procedure described for 7. An oil was obtained: 54% yield. ¹H-NMR (400 MHz, CDCl₃) δ: 7.53 (d, 2H), 7.38 (m, 13H), 6.89 (m, 4H), 5.03 (s, 2H), 4.61 (d, 1H), 4.07 (m, 2H), 3.84 (m, 1H), 3.80 (dd, 1H), 3.52 (m, 2H), 2.98 (m, 3H), 2.73 (dd, 1H), 2.07 (br s, 1H, exchangeable with D₂O).

ABBREVIATION USED

PD

Parkinson’s disease

DA

dopamine

5-HT

serotonin

CNS

central nervous system

α₁-AR

α₁-adrenoceptor

SAR

structure-activity relationship

ppm

part per million

TMS

tetramethylsilane