Abstract
A series of N,N’-disubstituted-2-nitroethene-1,1-diamine and N,N’-disubstituted-N’’-cyanoguanidine derivatives were prepared and evaluated for in vivo analgesic activity. The blood brain barrier (BBB) VolSurf model was used to predict the BBB permeation profiles of our synthesized compounds. Some compounds show both remarkable analgesic activity and good BBB permeation profiles, and these compounds might be developed for treatment of opioid tolerance and dependence.
Keywords: Agmatine derivatives, synthesis, analgesic activity, blood-brain barrier, opioid dependence
Introduction
Agmatine (1, Figure 1) is an endogenous ligand of imidazoline receptors [1], and is biologically active in the nervous system and many other tissues in mammals [2]. Previous research indicates that this compound, which is not able to interact with opioid receptors, plays an important role in regulating the pharmacological actions of opioids [3,4,5,6]. Agmatine has weak analgesic effects and shows biphasic modulation on opioid functions, which enhance opioid analgesia, but inhibit tolerance to and substance dependence on opioids. The mechanisms associated with the analgesic effect and biphasic modulation on opioid functions is by activation of imidazoline receptors on central nervous system [7,8]. These results suggest that agmatine might be developed for treatment of opioid tolerance and dependence, but the pharmacokinetic profile of agmatine, such as its low ability to cross the blood-brain barrier and its fast excretion (mostly due to its hydrophilicity), restricts its potential drug use [9,10].
Figure 1.
It is known that lipophilicity is an essential feature for the penetration of a molecule through the blood-brain barrier [11], consequently, the purpose of the present work was to synthesize several structurally-related agmatine derivatives with better lipophilicity and biological activity. We synthesized some derivatives of agmatine by substituting guanidine with 2-nitroethene-1,1-diamine or N-cyanoguanidine, and tested their analgesic activity in mice in order to find new potent compounds for treatment of opioid tolerance and dependence.
Results and Discussion
Chemistry
We used 1,1-bis(methylthio)-2-nitroethene as starting material, which was refluxed with one equivalent of amine to give the corresponding N-substituted-1-(methylthio)-2-nitroethenamines 2a-b. Then compounds 2 were reacted with the appropriate amine to obtain the corresponding N,N’-disubstituted -2-nitroethene-1,1-diamine derivatives 3a-j (Scheme 1) [12,13].
Scheme 1.
The synthesis of N,N’-disubstituted -2-nitroethene-1,1-diamines.
The preparation of N,N’-disubstituted-N’’-cyanoguanidine derivatives 5a-l was similar to that of 3a-j. First, dimethyl N-cyanodithioiminocarbonate was refluxed with one equivalent of amine to give the corresponding methyl N’-cyano-N-substituted-imidothiocarbamates 4a-d. Then compounds 4a-d were reacted with the second amine to give the derivatives 5a-l (Scheme 2) [14,15]. The structures of the compounds are presented in Table 1.
Scheme 2.
The synthesis of N,N’-disubstituted-N’’-cyanoguanidines.
Table 1.
Formulae of compounds 3a-i and 5a-j.
| Compd. | R1 | R2 | Compd. | R1 | R2 |
|---|---|---|---|---|---|
| 3a | CH3 | CH2C (CH3)2CH2N(CH3)2 | 5b | CH3 | (CH2)4NH2 |
| 3b | CH3 | (CH2)4NH2 | 5c | CH3 | (CH2)5NH2 |
| 3c | CH3 | (CH2)5NH2 | 5d | CH3 | (CH2)6NH2 |
| 3d | CH3 | (CH2)6NH2 | 5e | CH3 | (CH2)7NH2 |
| 3e | CH3 | (CH2)4CH3 | 5f | 3-pyridinylmethyl | CH2C(CH3)2CH2N(CH3)2 |
| 3f | CH3 | 4-piperidinobutyl | 5g | 3-pyridinylmethyl | (CH2)6NH2 |
| 3g | CH3 | CH2CCCH2NH2 | 5h | 3-pyridinylmethyl | (CH2)7NH2 |
| 3h | 3-pyridinylmethyl | CH3 | 5i | isobutyl | (CH2)6NH2 |
| 3i | 3-pyridinylmethyl | (CH2)4NH2 | 5j | isobutyl | (CH2)7NH2 |
| 3j | 3-pyridinylmethyl | (CH2)5NH2 | 5k | phenylethyl | (CH2)5NH2 |
| 5a | CH3 | CH2C(CH3)2CH2N(CH3)2 | 5l | phenylethyl | (CH2)7NH2 |
Analgesic activity
The mechanisms associated with the analgesic effect and biphasic modulation on opioid functions is similar, so the analgesic activity of synthesized derivatives can partly shows its ability for treatment of opioid tolerance and dependence. Analgesic activity was evaluated by measuring the effect of the tested compounds on acetic acid-induced writhing in mice. The results showed that compounds 3d, 3h, 5b, 5d, 5e, 5f and 5h have notable analgesic activity (see Table 2).
Table 2.
Inhibition on acetic acid-induced mice writhing and BBB profile as predicted by Volsurf.
| Compd | inhb.rate (%) | BBB prediction by Volsurf | Compd | inhb.rate (%) | BBB prediction by Volsurf |
|---|---|---|---|---|---|
| Saline | 0 | 5a | 27.0 | 0.79 | |
| Morphine | 100 | 5b | 57.3 | -0.51 | |
| Agmatine | 55.3 | -0.64 | 5c | 19.9 | -0.47 |
| 3a | 35.8* | 0.95 | 5d | 54.1** | -0.34 |
| 3b fumarate | 37.7 | -0.28 | 5e | 53.1 | -0.28 |
| 3c fumarate | 46.5 | -0.18 | 5f fumarate | 56.2* | 0.08 |
| 3d fumarate | 52.0* | -0.12 | 5g fumarate | 37.3 | -0.74 |
| 3e | 33.6* | 0.83 | 5h fumarate | 51.3 | -0.69 |
| 3f | 23.9 | 0.82 | 5i fumarate | 38.4* | -0.28 |
| 3g | 35.4 | -0.35 | 5j fumarate | 24.8 | -0.21 |
| 3h | 60.6* | 0.64 | 5k fumarate | 4.14 | -0.38 |
| 3i fumarate | 47.9 | -0.64 | 5l fumarate | 16.1* | -0.46 |
| 3j fumarate | 27.8 | -0.58 |
** P < 0.01, * P < 0.05, saline and morphine is the control.
Prediction of blood-brain barrier permeation of the compounds
The blood-brain barrier (BBB) is a complex cellular system and its function is to maintain the homeostasis of the central nervous system (CNS) by separating the brain from the systemic blood circulation. For drugs targeting the CNS, BBB penetration is a necessity. The BBB Volsurf model [16,17,18] was used to predict the permeation profile of our synthesized compounds and the results indicate that some are potentially good candidates (-0.15<BBB<1.00) for effective BBB permeation (Table 2). The model was able to correctly predict the BBB range for more than 75% of the compounds. Bearing in mind that BBB permeation is not only dependent on passive diffusion but also on active transport and metabolism, the results are very encouraging.
Conclusions
Ten compounds 3a-j and twelve compounds 5a-l were prepared as shown in Scheme 1 and Scheme 2. Compounds 3d, 3h and 5f present notable analgesic activity and good blood-brain barrier permeation profiles. Further research on these compounds and their potential use for treatment of opioid tolerance and dependence will be report in due course.
Experimental
General
1H-NMR (400 MHz) and 13C-NMR (100 MHz) spectra were recorded on a JNM-ECA-400 spectrometer in the solvents indicated. Mass spectral analyses were carried out using a Micromass ZabSpec or an API3000 mass spectrometer. Elemental analysis was carried at the CarloErba-1106 instrument. Melting points were recorded on an Electrothermal digital capillary melting point apparatus and are uncorrected. Column chromatography was performed with silica gel H (250-400 mesh).
General procedure for the preparation of compounds 2a-b
A solution of 1,1-bis(methylthio)-2-nitroethene (50 mmol) in absolute methanol (200 mL) was refluxed with one equivalent of amine for 8 h. After cooling to room temperature, the solvent was evaporated and the residue was recrystallized from ethanol/diethyl ether (1:6) to yield 2a-b.
N-Methyl-1-(methylthio)-2-nitroethenamine (2a) [19]: Yield 65%; mp: 113-115°C.
1-(Methylthio)-2-nitro-N-[(pyridin-3-yl)methyl]ethenamine (2b) [20]: Yield 67%; mp: 130-132°C; EI-MS: 225.0 (M)+.
General procedure for the preparation of compounds 3a-j and their fumarates
A mixture of N-substituted-1-(methylthio)-2-nitroethenamine 2 (1 mmol) and MeOH (15 mL) containing 1.5 equivalents of the appropriate amine was refluxed for 6h. After cooling to room temperature, the solvent was evaporated and the residue was purified by column chromatography to afford the product 3. One equivalent each of fumaric acid and 3 were dissolved in EtOH and then refluxed for 2 min. After cooling to room temperature diethyl ether was slowly added to the solution. The precipitate formed was filtered off to give the fumarate of 3.
N1,N1,2,2-Tetramethyl-N3-[1-(methylamino)-2-nitrovinyl]propane-1,3-diamine (3a): Yield 69%; mp: 99-100°C. 1H-NMR (D2O) δ: 0.97 (s, 6H), 2.26 (s, 6H), 2.36 (s, 2H), 2.90 (s, 3H), 3.14 (s, 2H), 6.86 (s, 1H); EI-MS: 231.1 (M+1)+; Anal. Calcd. for C10H22N4O2: C, 52.15; H, 9.63; N, 24.33. Found: C, 51.96; H, 9.73; N, 24.16.
N1-[1-(Methylamino)-2-nitrovinyl]butane-1,4-diamine (3b). Yield 56%; mp: 104-106°C; mp fumarate: 110-112 °C; 1H-NMR (D2O) δ: 1.47-1.62 (m, 4H), 2.65 (s, 2H), 2.90 (s, 3H), 3.28 (t, 2H), 6.88 (s, 1H); FAB-MS: 189.0 (M+1)+.
N1-[1-(Methylamino)-2-nitrovinyl]pentane-1,5-diamine (3c). Yield 57 %; mp: 110-112°C; 1H-NMR (D2O) δ: 1.35-1.48 (m, 6H), 2.61 (t, 2H), 2.89 (s, 3H), 3.26 (t, 2H), 6.87 (s, 1H); EI-MS: 203.0 (M+1)+; Anal. Calcd. for fumarate C8H18N4O2·C4H4O4: C, 45.28; H, 6.97; N, 17.60. Found: C, 44.94; H, 6.98; N, 17.26.
N1-[1-(Methylamino)-2-nitrovinyl]hexane-1,6-diamine (3d) [21]. Yield 55 %; mp: 111-113°C; 1H-NMR (D2O) δ: 1.15-1.45 (m, 8H), 2.61 (t, 2H), 2.89 (s, 3H), 3.26 (t, 2H), 6.87 (s, 1H); EI-MS: 217.2 (M+1)+; Anal. Calcd. for fumarate C9H20N4O2·C4H4O4: C, 46.98; H, 7.28; N, 16.86. Found: C, 46.73; H, 7.33; N, 16.58.
N-Methyl-2-nitro-N’-pentylethene-1,1-diamine (3e). Yield: 69 %; mp: 78-80°C; 1H-NMR (DMSO-D6) δ: 0.84 (m, 4H), 1.30 (t, 3H), 1.62 (s, 2H), 2.90 (s, 3H), 3.24 (t, 2H), 6.88 (s, 1H); EI-MS: 187.2 (M)+.
N-Methyl-2-nitro-N’-[4-(piperidin-1-yl)butyl]ethene-1,1-diamine (3f). Yield 39%; mp: 139-140°C; 1H-NMR (CDCl3) δ: 1.57-1.68 (m, 10H), 2.38 (s, 6H), 2.88 (d, 3H), 3.20 (s, 2H), 5.53 (s, 1H), 5.90 (s, 1H), 6.60 (s, 1H); FAB-MS: 257.2 (M+1)+.
N1-[1-(Methylamino)-2-nitrovinyl]but-2-yne-1,4-diamine (3g). Yield 43%; mp: 146-147°C; 1H-NMR (D2O) δ: 2.96 (s, 3H), 3.41 (s, 2H), 4.13 (s, 2H), 6.97 (s, 1H); FAB-MS: 185.2 (M+1)+.
N-Methyl-2-nitro-N’-[(pyridin-3-yl)methyl]ethene-1,1-diamine (3h) [22]. Yield: 61%; mp: 161-163°C; 1H-NMR (D2O) δ: 2.94 (s, 3H), 4.52 (s, 2H), 6.73 (s, 1H), 7.38 (dd, 1H), 7.73 (d, 1H), 8.41 (d, 2H); ESI-MS: 209.2 (M+1)+; Anal. Calcd. for C9H12N4O2: C, 51.92; H, 5.81, N 26.91. Found: C, 51.88; H, 5.92; N, 26.67.
N1-[1-((Pyridin-3-yl)methylamino)-2-nitrovinyl]butane-1,4-diamine (3i). Yield: 61%; mp fumarate: 197-198°C; 1H-NMR (D2O) δ: 1.53 (s, 4H), 2.84 (s, 2H), 3.22 (s, 2H), 4.46 (s, 2H), 6.34 (s, 1H), 7.30 (t, 1H), 7.65 (d, 1H), 8.32 (s, 2H); EI-MS: 266.0 (M+1)+; Anal. Calcd. for fumarate C12H19N5O2·1/2 C4H4O4: C, 52.00; H, 6.55; N, 21.66. Found: C, 51.89; H, 6.61; N, 21.40.
N1-[1-((Pyridin-3-yl)methylamino)-2-nitrovinyl]pentane-1,5-diamine (3j). Yield: 55 %; mp fumarate: 182-184°C; 1H-NMR (D2O) δ: 1.48 (s, 6H), 2.79 (s, 2H), 3.19 (s, 2H), 4.47 (s, 2H), 6.34 (s, 1H), 7.31 (t, 1H), 7.66 (d, 1H), 8.33 (s, 2H). EI-MS: 280.0 (M+1)+.
General procedure for the preparation of 4a-d
A solution of dimethyl N-cyanodithioiminocarbonate (50 mmol) in absolute methanol (200 mL) was refluxed with one equivalent of amine (50 mmol) for 6 h. After cooling to room temperature, the solvent was evaporated and the residue was recrystallized from ethanol/diethyl ether (1:6) to yield 4a-l.
Methyl N’-cyano-N-methyl-imidothiocarbamate (4a) [23]: Yield: 59 %; mp: 202-203°C.
Methyl N’-cyano-N-[(pyridin-3-yl)methyl]-imidothiocarbamate (4b) [24]: Yield: 63%; mp: 155-157°C; 1H-NMR (DMSO-D6) δ: 2.62 (s, 3H), 4.51 (s, 2H), 7.36 (dd, 1H), 7.70 (d, 1H), 8.48-8.52 (m, 2H), 8.91 (s, 1H).
Methyl N’-cyano-N-isobutyl-imidothiocarbamate (4c) [25]: Yield: 67 %; mp: 119-121°C.
Methyl N’-cyano-N-phenylethyl-imidothiocarbamate (4d): Yield: 61 %; mp: 173-174°C (Lit. [26] 172-175°C).
General procedure for the preparation of 5a-l and their fumarates
A mixture of methyl N’-cyano-N-substituted-imidothiocarbamate 4a-d (1 mmol) and MeOH (15 mL) containing 1.5 equivalent of amine was refluxed for 6h. After cooling to room temperature, the solvent was evaporated and the residue was purified by column chromatography to afford the products 5a-l. One equivalent each of fumaric acid and 5a-l was dissolved in EtOH and then refluxed for 2 min. After cooling to room temperature diethyl ether was added slowly to the solution. The precipitate formed was filtered off to give the corresponding fumarate of 5a-l.
N’’-Cyano-N-[3-(dimethylamino)-2,2-dimethylpropyl]-N’-methylguanidine (5a): Yield 73%; mp: 124-126°C; 1H-NMR (D2O) δ: 0.97 (s, 6H), 2.33 (s, 6H), 2.36 (s, 2H), 2.77 (s, 3H), 3.09 (s, 2H); EI-MS: 211.1 (M)+; Anal. Calcd. for C10H21N5: C, 56.84; H, 10.02; N, 33.14. Found: C, 57.00; H, 10.26; N, 33.13.
N-(4-Aminobutyl)-N’’-cyano-N’-methylguanidine (5b) [27]: Yield 57%; mp: 113-115°C; 1H-NMR (D2O) δ: 1.50-1.58 (m, 4H), 2.67 (t, 2H), 2.78 (s, 3H), 3.30 (t, 2H); EI-MS: 169.0 (M)+; Anal. Calcd. for C7H15N5: C, 49.68; H, 8.93; N, 41.38. Found: C, 49.99; H, 8.99; N, 41.18.
N-(5-Aminopentyl)-N’’-cyano-N’-methylguanidine (5c): Yield 56%; mp: 112-114 °C; 1H-NMR (D2O) δ: 1.35-1.37 (m, 2H), 1.50-1.57 (m, 4H), 2.64 (t, 2H), 2.77 (s, 3H), 3.18 (t, 2H); EI-MS: 182.0 (M-1)+; Anal. Calcd. for C8H17N5: C, 52.43; H, 9.35; N,38.22. Found: C, 52.66; H, 9.46; N, 38.02.
N-(6-Aminohexyl)-N’’-cyano-N’-methylguanidine (5d): Yield 53%; mp: 78-80°C; 1H-NMR (D2O) δ: 1.35 (m, 4H), 1.48-1.55 (m, 4H), 2.62 (t, 2H), 2.78 (s, 3H), 3.18 (t, 2H); EI-MS: 197.0 (M)+.
N-(7-Aminoheptyl)-N’’-cyano-N’-methylguanidine (5e): Yield 49%; mp: 83-86°C; 1H-NMR (D2O) δ: 1.17-1.33 (m, 10H), 2.41 (t, 2H), 2.58 (s, 3H), 2.98 (t, 2H); EI-MS: 211.0 (M)+; Anal. Calcd. for C10H21N5: C, 56.84; H, 10.02; N, 33.14. Found: C, 56.69; H, 10.17; N, 32.66.
N’’-Cyano-N-[3-(dimethylamino)-2,2-dimethylpropyl]-N’-[(pyridin-3-yl)methyl]guanidine (5f): Yield 68%; mp fumarate: 119-120°C; 1H-NMR (D2O) δ: 0.74 (s, 6H), 2.70-2.76 (m, 8H), 3.00 (s, 2H), 4.43 (s, 2H), 6.33 (m, 2H), 7.59 (m, 1H), 8.05 (m, 1H), 8.39-8.44 (m, 2H); EI-MS: 288.0(M)+;
N-(6-Aminohexyl)-N’’-cyano-N’-[(pyridin-3-yl)methyl]guanidine (5g): Yield 61%; mp fumarate: 158-159°C; 1H-NMR (D2O) δ: 1.13 (m, 4H), 1.36-1.43 (m,4H), 2.75 (t, 2H), 3.03 (t, 2H), 4.40 (s, 2H), 6.38 (s, 2H), 7.62 (m, 1H), 8.04 (m,1H) , 8.41 (m, 2H); EI-MS: 274.2 (M)+; Anal. Calcd. for fumarate C14H22N6·C4H4O4: C, 55.37; H, 6.71; N, 21.52. Found: C, 55.24; H, 6.85; N, 21.42.
N-(7-Aminoheptyl)-N’’-cyano-N’-[(pyridin-3-yl)methyl]guanidine (5h): Yield 66%; mp fumarate: 149-150°C; 1H-NMR (D2O) δ: 1.11 (m, 6H), 1.32-1.45 (m, 4H), 2.75 (t, 2H), 3.02 (t, 2H), 4.38 (s, 2H), 6.36 (s, 2H), 7.55 (m, 1H), 7.96 (m, 1H) , 8.38 (m, 2H); EI-MS: 288.4 (M)+; Anal. Calc. for fumarate C15H24N6·C4H4O4: C, 56.42; H, 6.98; N, 20.78. Found: C, 56.56; H, 7.20; N, 21.22.
N-(6-Aminohexyl)-N’’-cyano-N’-isobutylguanidine (5i): Yield 57%; mp fumarate: 154-157°C; 1H-NMR (D2O) δ: 0.74 (d, 6H), 1.22 (m, 4H), 1.40-1.50 (m, 4H), 1.52 (m, 1H), 2.84 (dd, 4H), 3.05 (t, 2H), 6.41 (s, 2H); EI-MS: 239.2 (M)+; Anal. Calcd. for fumarate C12H25N5·C4H4O4: C, 54.07; H, 8.22; N, 19.70. Found: C, 54.60; H, 8.09; N, 19.97.
N-(7-Aminoheptyl)-N’’-cyano-N’-isobutylguanidine (5j): Yield 51%; mp fumarate: 113-115°C; 1H-NMR (D2O) δ: 0.74 (d, 6H), 1.21 (s, 4H), 1.39-1.51 (m, 4H), 1.69 (m, 1H), 2.84 (dd, 4H), 3.05 (t, 2H), 6.54 (s, 2H); EI-MS: 253.2 (M)+; Anal. Calcd. for fumarate C13H27N5·C4H4O4: C, 55.27; H, 8.46; N, 18.96. Found: C, 55.11; H, 8.55; N, 19.14.
N-(5-Aminopentyl)-N’’-cyano-N’-phenethylguanidine (5k): Yield 55%; mp fumarate: 155-156°C; 1H-NMR (D2O) δ: 1.09-1.22 (m,4H), 1.42 (dd, 2H), 2.67-2.87 (m, 6H), 3.28 (t, 2H), 6.49 (s, 2H), 7.09-7.19 (m, 5H); EI-MS: 273.2 (M)+; Anal. Calc. for fumarate C15H23N5·C4H4O4: C, 58.60; H, 6.99; N, 17.98. Found: C, 58.06, H, 7.09; N, 17.72.
N-(7-Aminoheptyl)-N’’-cyano-N’-phenethylguanidine (5l): Yield 60%; mp fumarate: 165-166°C; 1H-NMR (D2O) δ: 1.13-1.20 (m, 8H), 1.45 (m, 2H), 2.67-2.85 (m, 6H), 3.28 (t, 2H), 6.49 (s, 2H), 7.08-7.19 (m, 5H); EI-MS: 301.2 (M)+; Anal. Calcd. for fumarate C17H27N5·C4H4O4; C, 60.41; H, 7.48; N, 16.77; Found: C, 60.16; H, 7.61; N, 16.76.
Analgesic activity
Male and Female (1:1) Kunming mice (weighing 18-22 g) were used to test the analgesic activity. The tests were carried out by administering the compounds orally at a dose of 40 mg/kg, and each compound was tested on 10 mice. Thirty minutes later, the animals were injected intraperitoneally (ip) with 0.4 mL/mouse of a 0.6% acetic acid solution and writhes were counted during the following 15 min. The mean number of writhes for each experimental group and percent decrease compared with control group (10 mice treated with saline) were calculated.
Acknowledgements
The authors wish to express their gratitude to the National Basic Research Program of China (973 project: 2003CB515400) for financial support of this research.
Footnotes
Sample availability: Available from the authors.
References
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