Conolidine

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Conolidine
Conolidine structure.png
Names
Systematic IUPAC name
(4E,5S)-4-Ethylidene-1,4,5,7-tetrahydro-2,5-ethanoazocino[4,3-b]inden-6(3H)-one
Identifiers
3D model (JSmol)
ChemSpider
PubChem CID
UNII
  • InChI=1S/C17H18N2O/c1-2-11-9-19-8-7-12(11)17(20)16-14(10-19)13-5-3-4-6-15(13)18-16/h2-6,12,18H,7-10H2,1H3/b11-2-/t12-/m0/s1 X mark.svgN
    Key: DBGBUYFOJXOYNY-RENATIMJSA-N X mark.svgN
  • InChI=1/C17H18N2O/c1-2-11-9-19-8-7-12(11)17(20)16-14(10-19)13-5-3-4-6-15(13)18-16/h2-6,12,18H,7-10H2,1H3/b11-2-/t12-/m0/s1
    Key: DBGBUYFOJXOYNY-RENATIMJBD
  • CC(=O)NC(=NCCC[C@H]1C(=O)N2CCC[C@@H]2C(=O)N[C@H]3C[C@H](N(C3=O)[C@H](C(=O)N[C@H](C(=O)N1)CCCC(=O)O)CC4=CN=CN4)O)N
Properties
C17H18N2O
Molar mass 266.344 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Tabernaemontana divaricata Tabernaemontana divaricata.jpg
Tabernaemontana divaricata

Conolidine is an indole alkaloid. Preliminary reports suggest that it could provide analgesic effects with few of the detrimental side-effects associated with opioids such as morphine, though at present it has only been evaluated in mouse models.

Contents

Conolidine was first isolated in 2004 from the bark of the Tabernaemontana divaricata (crape jasmine) shrub which is used in traditional Chinese medicine. [1]

The first asymmetric total synthesis of conolidine was developed by Micalizio and coworkers in 2011. [2] This synthetic route allows access to either enantiomer (mirror image) of conolidine via an early enzymatic resolution. Notably, evaluation of the synthetic material resulted in the discovery that both enantiomers of the synthetic compound show analgesic effects. [3]

Syntheses

The Micalizio route (2011) achieved the end product in 9 steps from a commercially available acetyl-pyridine. Notable reactions include a [2,3]-Still-Wittig rearrangement and a conformationally-controlled intramolecular Mannich cyclization.

The Weinreb group (2014) used a conjugative addition of an indole precursor to an oxime-substituted nitrosoalkene to generate the tetracyclic skeleton of conolidine in 4 steps. [4]

Takayama and colleagues (2016) synthesized conolidine and apparicine through a gold(I)-catalyzed exo-dig synthesis of a racemic piperidinyl aldehyde. [5]

Ohno and Fujii (2016) accessed the tricyclic pre-Mannich intermediate through a chiral gold(I) catalyzed cascade cyclization. [6]

In 2019, a six step synthesis was developed using Gold-catalyzed cyclization reaction and Pictet-Spengler reaction having 19% overall yield. [7]

Pharmacology

In 2011, the Bohn lab noted antinociception against both chemically induced and inflammation-derived pain, and experiments indicated lack of opioid receptor modulation, but were unable to define a particular target. A 2019 study by a cross-site Australian and U.S. group discovered through cultured neuronal networks that conolidine may inhibit the Ca v2.2 channel, a mechanism seen in molecules like conotoxin. The group was unable to rule out partial polypharmacology against other targets. [8]

Conolidine has been discovered to bind to novel opioid receptor ACKR3 (CXCR7). [9] [10] By binding to this receptor, the endogenous opioid peptides (such as endorphins and enkephalins) cannot be trapped thus increasing availability of those peptides to their target sites. [9] [10]

Derivatives

DS54360155, a novel compound with a unique and original bicyclic skeleton, is more a potent analgesic than conolidine in mice. [11] DS39201083 [12] and DS34942424 [13] are other similar derivatives. They all lack mu-opioid activity. The researchers who found conolidine binding site ACKR3/CKCR7 also developed a synthetic analogue of it called RTI-5152-12. It displays an even greater activity on that receptor. [9]

See also

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References

  1. ↑ Kam, T.-S., Pang, H. S., Choo, Y. M., Komiyama, K. (Apr 2004). "Biologically Active Ibogan and Vallesamine Derivatives from Tabernaemontana divaricata". Chemistry & Biodiversity. 1 (4): 646–656. doi:10.1002/cbdv.200490056. PMID   17191876. S2CID   12805328.
  2. ↑ Tarselli, M. A., Raehal, K. M., Brasher, A. K., Groer, C., Cameron, M. D., Bohn, L. M., Micalizio, G. C. (2011). "Synthesis of Conolidine, a Potent Non-Opioid Analgesic for Tonic and Persistent Pain". Nature Chemistry. 3 (6): 449–453. Bibcode:2011NatCh...3..449T. doi:10.1038/nchem.1050. PMID   21602859.
  3. ↑ Ball, P. (May 2011). "Compound Offers Pain Relief Without the Complications". Nature. doi:10.1038/news.2011.313.
  4. ↑ Chauhan, P.S., Weinreb, S.M. (2014). "Convergent Approach to the Tetracyclic Core of the Apparicine Class of Indole Alkaloids via a Key Intermolecular Nitrosoalkene Conjugate Addition". Journal of Organic Chemistry. 79 (13): 6389–6393. doi:10.1021/jo501067u. PMID   24927230.
  5. ↑ Takanashi, N., Suzuki, K., Kitajima, M., Takayama, H. (2016). "Total Synthesis of Conolidine and Apparicine". Tetrahedron Letters. 57 (3): 375–378. doi:10.1016/j.tetlet.2015.12.029.
  6. ↑ Noae, S., Yoshida, Y., Oishi, S., Fujii, N., Ohno, H. (2016). "Total Synthesis of (+)-Conolidine by the Gold(I)-Catalyzed Cascade Cyclization of a Conjugated Enyne" (PDF). Journal of Organic Chemistry. 81 (13): 5690–5698. doi:10.1021/acs.joc.6b00720. hdl: 2433/241631 . PMID   27276227. S2CID   6270027.
  7. ↑ Chen G, Wang C, Zou L, Zhu J, Li Y, Qi C (November 2019). "Six-Step Total Synthesis of (±)-Conolidine". Journal of Natural Products . 82 (11): 2972–2978. doi:10.1021/acs.jnatprod.9b00302. PMID   31686504. S2CID   207899726.
  8. ↑ Petrou S, Halgamuge S, Reid CA, Osborne PB, M. Varney, Li M, Pachernegg S, Morrisroe E, Berecki G (2019-01-15). "Discovering the pharmacodynamics of conolidine and cannabidiol using a cultured neuronal network based workflow". Scientific Reports. 9 (1): 121. Bibcode:2019NatSR...9..121M. doi:10.1038/s41598-018-37138-w. ISSN   2045-2322. PMC   6333801 . PMID   30644434.
  9. 1 2 3 “The natural analgesic conolidine targets the newly identified opioid scavenger ACKR3/CXCR7” by Martyna Szpakowska, Ann M. Decker, Max Meyrath, Christie B. Palmer, Bruce E. Blough, Ojas A. Namjoshi & Andy Chevigné. Signal Transduction and Targeted Therapy
  10. 1 2 Szpakowska M, Decker AM, Meyrath M, Palmer CB, Blough BE, Namjoshi OA, Chevigné A (June 2021). "The natural analgesic conolidine targets the newly identified opioid scavenger ACKR3/CXCR7". Signal Transduct Target Ther. 6 (1): 209. doi:10.1038/s41392-021-00548-w. PMC   8169647 . PMID   34075018.
  11. ↑ Arita T, Asano M, Kubota K, Domon Y, Machinaga N, Shimada K (December 2019). "Discovery of a novel bicyclic compound, DS54360155, as an orally potent analgesic without mu-opioid receptor agonist activity". Bioorganic & Medicinal Chemistry Letters . 29 (23): 126748. doi:10.1016/j.bmcl.2019.126748. PMID   31676224. S2CID   207832139.
  12. ↑ Arita T, Asano M, Kubota K, Domon Y, Machinaga N, Shimada K (August 2019). "Discovery of conolidine derivative DS39201083 as a potent novel analgesic without mu opioid agonist activity". Bioorganic & Medicinal Chemistry Letters . 29 (15): 1938–1942. doi:10.1016/j.bmcl.2019.05.045. PMID   31147104. S2CID   171092814.
  13. ↑ Arita T, Asano M, Kubota K, Domon Y, Machinaga N, Shimada K (November 2020). "Discovery of DS34942424: An orally potent analgesic without mu opioid receptor agonist activity". Bioorganic & Medicinal Chemistry . 28 (21): 115714. doi:10.1016/j.bmc.2020.115714. PMID   33065431. S2CID   223556538.


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