Structure-Activity Relationships for the Anaesthetic and Analgaesic Properties of Aromatic Ring-Substituted Ketamine Esters
"> Figure 1
<p>Ketamine, tiletamine.</p> "> Figure 2
<p>Known norketamine analogues.</p> "> Scheme 1
<p>Synthesis of ketamine alkyl esters; Reagents and conditions: (i) Br(CH<sub>2</sub>)<sub>2</sub>CO<sub>2</sub><span class="html-italic"><sup>i</sup></span>Pr, K<sub>2</sub>CO<sub>3</sub>, KI, MeCN, reflux 12–48h; (ii) Br(CH<sub>2</sub>)<sub>4</sub>CO<sub>2</sub>Me, KI, MeCN, reflux 12–48h.</p> "> Scheme 2
<p>Synthesis of ring-substituted norketamines <b>21, 22, 30b,c, e–i, k–p.</b> R = : <b>a</b>, H; <b>b</b>, 2-F; <b>c</b>, 3-Cl; <b>d</b>, 4-Cl; <b>e</b>, 2-Me; <b>f</b>, 3-Me; <b>g</b>, 4-Me; <b>h</b>, 2-OMe; <b>i</b>, 3-OMe; <b>j</b>, 4-OMe; <b>k</b>, 2-CF<sub>3</sub>; <b>l</b>, 3-CF<sub>3</sub>, <b>m</b>, 4-CF<sub>3</sub>; <b>n</b>, 2-OCF<sub>3</sub>; <b>o</b>, 3-OCF<sub>3</sub>; <b>p</b>, 4-OCF<sub>3</sub>; Reagents and conditions: (i) NH<sub>2</sub>NMe<sub>2</sub>, EtOH, reflux 18 h; (ii) (a) MeI, MeCN, 40 °C for 2 h then 70 °C for 3 h; (iii) NaOEt, EtOH, reflux, 1 h.</p> "> Scheme 3
<p>Synthesis of nortiletamine; Reagents and Conditions: (i) BzCl, pyridine, n-hexane-CH<sub>2</sub>Cl<sub>2</sub> (10:1), 4 h r.t., then TFAA, CH<sub>2</sub>Cl<sub>2</sub>, r.t. 12 h, 89%; (ii) thiophene, <span class="html-italic">n</span>-BuLi, MeAlCl, THF, r.t. 30 min, then <b>32</b>, reflux, 3 h, 66%; (iii) NaOH (5% in MeOH), r.t. 12 h; (iv) Jones reagent, 84%.</p> ">
Abstract
:1. Introduction
2. Chemistry and Biology
2.1. Chemistry
2.2. Biology
3. Results and Discussion
Conclusions
4. Experimental
4.1. Chemistry
4.2. Synthesis of Ring-Substituted Norketamine Analogues. (Scheme 2)
4.3. Synthesis of Nortiletamine (35) (Scheme 3).
4.4. Synthesis of Ketamine Esters (Example) (Scheme 1).
4.5. Biology
4.5.1. Animals
4.5.2. Anaesthetic Assessment Protocol
Supplementary Materials
Author Contributions
Acknowledgments
Conflicts of Interest
Abbreviations
DCM | Dichloromethane |
LORR | Loss of righting reflex |
NMDA | N-methyl-D-aspartate |
PWR | Pedal withdrawal reflex score |
TFAA | Trifluoroacetic acid anhydride. |
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No | X | n | R | Sedation | Analgaesia | Rat | NMDA | Behavioural dysfunction | |||
---|---|---|---|---|---|---|---|---|---|---|---|
LORR a (mg/kg) (SEM) | RORR b (sec) (SEM) | potency c (mg/kg) (SEM) | cTFL d (sec) | t½ e (min) | IC50 (μM)f | Score g (SEM) | Duration h (SEM) | ||||
1 | 2-Cl | 3 | Me | 21 (4) | 1075 (89) | 28 | 671 | 44.4 | 0.7 | 3 (0) | 3 (1) |
3a | H | 3 | A | >200 (0) | N/Ai | >200 (0) | 0 | >1000 | 0.5 (0.7) | 0 (0) | |
3b | H | 3 | B | 40 (5) | 78 (22) | 45 (5) | 0 | 9.9 | 1 (0) | 2 (0) | |
4a | 2-F | 3 | A | 59 (10) | 64 (7) | 62 (6) | 1297 | 249 | 1 (0) | 1 (0) | |
4b | 2-F | 2 | B | 35 (4) | 84 (20) | 40 (5) | 11 | 3.1 | 3 (1.4) | 4 (0) | |
5aj | 2-Cl | 3 | A | 33 (10) | 83 (33) | 37 (11) | 1384 | 3.4 | 134 | 2 (1) | 1 (0) |
5bj | 2-Cl | 3 | B | 34 (12) | 99 (28) | 44 (17) | 374 | 0.7 | 3.2 | 2 (0) | 1 (0) |
6a | 2-Me | 3 | A | >200 (0) | N/A | >200 (0) | 393 | 428 | 0 (0) | 0 (0) | |
6b | 2-Me | 3 | B | 37 (2) | 85 (14) | 43 (3) | 91 | 3.4 | 1 (0) | 2 (1) | |
7a | 2-OMe | 1 | A | >200 (0) | N/A | >200 (0) | 313 | 172 | 0 (0) | 0 (0) | |
7b | 2-OMe | 2 | B | 34 (9) | 135 (12) | 49 (11) | 2332 | >1000 | 3 (1) | 2 (0) | |
8a | 2-CF3 | 2 | A | 64 (12) | 58 (4) | 64 (12) | 652 | 290 | 2 (1) | 1 (0) | |
8b# | 2-CF3 | 2 | B | 154 (42) | 66 (8) | 156 (45) | 1864 | 128 | 1 (0) | 1 (0) | |
9a | 2-OCF3 | 1 | A | 62 (0) | 65 (0) | 62 (0) | 80 | 184 | 1 (0) | 1 (0) | |
9b | 2-OCF3 | 2 | B | >200 (0) | N/A | >200 (0) | 119 | 121 | 3 (1) | 3 (0) | |
10a | 3-Cl | 3 | A | 67 (21) | 10 (1) | 58 (11) | 332 | 164 | 1 (0) | 1 (0) | |
10b | 3-Cl | 3 | B | 51 (6) | 114 (46) | 61 (4) | 54 | 13 | 3 (1) | 2 (0) | |
11a | 3-Me | 2 | A | 38 (4) | 108 (39) | 50 (5) | 63 | 466 | 2 (1) | 1 (0) | |
11b | 3-Me | 2 | B | 39 (6) | 137 (32) | 43 (6) | 104 | 5.2 | 2 (1) | 1 (0) | |
12a | 3-OMe | 1 | A | 79 (0) | 10 (0) | 83 (0) | 284 | 201 | 2 (0) | 1 (0) | |
12b | 3-OMe | 2 | B | 50 (8) | 120 (3) | 58 (6) | 210 | 5.6 | 3 (1.4) | 4 (0) | |
13ak | 3-CF3 | 1 | A | >200 (0) | N/A | >200 (0) | 208 | 229 | 0 (0) | 0 (0) | |
13b# | 3-CF3 | 2 | B | >200 (0) | N/A | >200 (0) | 8 | 172 | 0 (0) | 0 (0) | |
14a | 3-OCF3 | 2 | A | >200 (0) | N/A | >200 (0) | 274 | 211 | 0 (0) | 0 (0) | |
14b | 3-OCF3 | 3 | B | >200 (0) | N/A | >200 (0) | 444 | 57 | 0 (0) | 0 (0) | |
15a | 4-Cl | 3 | A | 99 (43) | 15 (9) | >200 (0) | 491 | 129 | 2 (1) | 1 (0) | |
15b | 4-Cl | 3 | B | 89 (40) | 82 (40) | 100 (23) | 576 | 101 | 3 (1) | 3 (0) | |
16a | 4-Me | 1 | A | 47 (0) | 10 (0) | 52 (0) | 650 | 161 | 1 (0) | 1 (0) | |
16b | 4-Me | 2 | B | 50 (6) | 75 (11) | 55 (9) | 0 | 23 | 1 (0) | 0 (0) | |
17a | 4-OMe | 2 | A | >200 (0) | N/A | >200 (0) | 167 | 396 | 0 (0) | 0 (0) | |
17b | 4-OMe | 1 | B | Seizure | 551 | 94.1 | 3 (0) | 3 (0) | |||
18a# | 4-CF3 | 1 | A | >200 (0) | N/A | >200 (0) | 412 | 438 | 0 (0) | 0 (0) | |
18b# | 4-CF3 | 2 | B | >200 (0) | N/A | >200 (0) | 37 | 470 | 0 (0) | 0 (0) | |
19a | 4-OCF3 | 1 | A | >200 (0) | N/A | >200 (0) | 166 | 314 | 0 (0) | 0 (0) | |
19b | 4-OCF3 | 1 | B | >200 (0) | N/A | >200 (0) | 194 | 597 | 0 (0) | 0 (0) | |
20a | thioph | 3 | A | >200 (0) | N/A | >200 (0) | 362 | 157 | 1 (1) | 1 (0) | |
20b | thioph | 2 | B | 52 (6) | 10 (2) | 74 (7) | 196 | 8.9 | 4 (0) | 1 (0) |
(1) General | Exophthalmos |
Increased respiration | |
Decreased respiration | |
(2) Motor | Hunched posturing |
Subdued | |
Increased/decreased body tone | |
Increased/decreased locomotor activity | |
(3) Reactivity | Increased irritability on gentle handling |
Decreased irritability on gentle handling | |
Rearing | |
(4) Stereotypical behaviours | Head weaving |
Ataxia/decreased co-ordination | |
Splayed hind legs |
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Dimitrov, I.V.; Harvey, M.G.; Voss, L.J.; Sleigh, J.W.; Bickerdike, M.J.; Denny, W.A. Structure-Activity Relationships for the Anaesthetic and Analgaesic Properties of Aromatic Ring-Substituted Ketamine Esters. Molecules 2020, 25, 2950. https://doi.org/10.3390/molecules25122950
Dimitrov IV, Harvey MG, Voss LJ, Sleigh JW, Bickerdike MJ, Denny WA. Structure-Activity Relationships for the Anaesthetic and Analgaesic Properties of Aromatic Ring-Substituted Ketamine Esters. Molecules. 2020; 25(12):2950. https://doi.org/10.3390/molecules25122950
Chicago/Turabian StyleDimitrov, Ivaylo V., Martyn G. Harvey, Logan J. Voss, James W. Sleigh, Michael J. Bickerdike, and William A. Denny. 2020. "Structure-Activity Relationships for the Anaesthetic and Analgaesic Properties of Aromatic Ring-Substituted Ketamine Esters" Molecules 25, no. 12: 2950. https://doi.org/10.3390/molecules25122950