Alazocine – Wikipedia

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Synthetic opioid analgesic

Alazocine
Alazocine.svg
Other names SKF-10047; WIN-19631; N -Allylnormetazocine; NANM; NAN; ANMC; 2′-Hydroxy-5,9-dimethyl-2-allyl-6,7-benzomorphan
ATC code

  • (±)-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(2-propen-1-yl)-2,6-methano-3-benzazocin-8-ol

CAS Number
  • 825594-24-9 checkAND
    34061-23-9 (hydrochloride)
    14198-28-8 ((–)-isomer)
    58640-82-7 ((+)-isomer)
    74957-58-7 ((–)-isomer HCl )
    133005-41-1 ((+)-isomer HCl )
Pubchem CID
ChemSpider
SOME
Clock
CompTox Dashboard ( EPA )
Echa infocard 100.162.264 Edit this at Wikidata
Formula C 17 H 23 N O
Molar mass 257.377 g · mol −1
3D model (JSMOL)

  • CC1C2CC3=C(C1(CCN2CC=C)C)C=C(C=C3)O

  • InChI=1S/C17H23NO/c1-4-8-18-9-7-17(3)12(2)16(18)10-13-5-6-14(19)11-15(13)17/h4-6,11-12,16,19H,1,7-10H2,2-3H3 checkY
  • Key:LGQCVMYAEFTEFN-UHFFFAOYSA-N checkY
☒N checkAND  (what is this?) (verify)

Alazocine (developmental code name SKF -10047 ), also known more commonly as N -allylnormetazocine ( Soul ), is a synthetic opioid analgesic of the benzomorphan family related to metazocine, which was never marketed. [first] [2] [3] In addition to its opioid activity, the drug is a sigma receptor agonist, and has been used widely in scientific research in studies of this receptor. [4] [5] Alazocine is described as a potent analgesic, psychotomimetic or hallucinogen, and opioid antagonist. [2] Moreover, one of its enantiomers was the first compound that was found to selectively label the σ first receptor, and led to the discovery and characterization of the receptor. [4] [5]

Pharmacology [ edit ]

Pharmacodynamics [ edit ]

Alazocine shows stereoselectivity in its pharmacodynamics. [6] The (–)-enantiomer is a non-selective and high-affinity ligand of the μ-, κ-, and δ-opioid receptors (K i = 3.0, 4.7, and 15 nM in guinea pig brain membranes) with very low affinity for the sigma σ first receptor (K i = 1,800–4,657 nM in guinea pig brain membranes). [6] [7] It acts as a moderate-efficacy partial agonist of the κ-opioid receptor (K i = 0.4 nM, EC 50 = 24 nM, and E max = 66% for (±)-alazocine against the mouse receptor transfected in HEK293 cells) [8] and as an antagonist of the μ-opioid receptor (K i = 1.15 nM for (±)-alazocine against the mouse receptor transfected in HEK293 cells). [9] It is also an agonist of the δ-opioid receptor with far lower potency (K i = not reported, IC 50 = 184 nM, and I max = 68% for (±)-alazocine against the mouse receptor transfected in HEK293 cells). [ten]

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Conversely, the (+)-stereoisomer has little affinity for the opioid receptors (K i for 1,900 nM, 1,600 nM, and 19,000 nM for the μ-, κ-, δ-opioid receptors in guinea pig brain membranes) and instead is a selective and high-affinity agonist of the σ first receptor (K i = 48–66 nM in guinea pig brain membranes). [6] [7] However, the (+)-enantiomer also shows moderate affinity for the dizocilpine (MK-801) or phencyclidine (PCP) site of the NMDA receptor (K i = 587 nM in rat brain membranes relative to 45 nM for the σ first receptor) and, hence, is an uncompetitive NMDA receptor antagonist as well at higher concentrations. [11] As such, (+)-alazocine is only modestly selective as a ligand of the σ first receptor. [11]

Both enantiomers of alazocine have very low affinity for the sigma σ 2 receptor (K i = 13,694 nM and 4,581 nM for the (+)- and (–)-enantiomers, respectively, in rat brain membranes or rat PC12 cells). [11] [7] [5] As such, due to its high affinity for the σ first receptor, (+)-alazocine can be used to distinguish between the two sigma receptor subtypes in scientific research, for instance in radioligand binding assays. [11] [5]

Taken together, (–)-alazocine is a selective partial agonist of the κ-opioid receptor, antagonist of the μ-opioid receptor, and to a far lesser extent agonist of the δ-opioid receptor [8] [9] [ten] with very low affinity for the sigma receptors, while (+)-alazocine is a selective agonist of the sigma σ first receptor and to a lesser (~10-fold) extent antagonist of the NMDA receptor with low affinity for the opioid and sigma σ 2 receptors. [6] [7] [11] [5]

History [ edit ]

Alazocine was one of the early members of the benzomorphan family of opioid analgesics to be investigated. [first] It was first described in the scientific literature in 1961. [twelfth] Its development resulted from nalorphine (N-allylnormorphine), a potent analgesic and opioid antagonist with similar pharmacology which had been introduced in the mid-1950s. [first] Alazocine was found to produce strong psychotomimetic effects in humans, and it was not further developed for clinical use. [13] [first] Subsequently, other benzomorphans, such as pentazocine (an N -dimethylallylbenzomorphan), cyclazocine (an N -cyclopropylmethylbenzomorphan), and phenazocine (an N -phenylethylbenzomorphan), were developed, and some have been marketed for use as analgesics. [first]

The sigma σ first receptor was named in 1976 and (+)-alazocine was described as its prototypical ligand. [13] [14] [15] The receptor was initially thought to be an opioid receptor, and then was confused with the NMDA receptor for a time, but was ultimately distinguished from them both. [13] [14] [5] The psychotomimetic effects of alazocine and the other benzomorphans were initially attributed incorrectly to agonism of the σ first receptor; subsequent research established that the effects are in fact caused by agonism of the κ-opioid receptor and/or antagonism of the NMDA receptor. [13] [5] The sigma σ 2 receptor was discovered and named in 1990, and was identified in part due to the dramatically reduced affinity of alazocine for the receptor relative to the σ first receptor (in contrast to non-selective ligands like haloperidol, ditolylguanidine, and (+)-3-PPP, which show similar affinity for both subtypes). [7]

References [ edit ]

  1. ^ a b c d It is CASY AF, PARFITT RT (29 June 2013). Opioid Analgesics: Chemistry and Receptors . Springer Science & Business Media. pp. 176–178, 420–421. ISBN  978-1-4899-0585-7 .
  2. ^ a b Keats AS, Telford J (1964). “Narcotic Antagonists as Analgesics”. Molecular Modification in Drug Design . Advances in Chemistry. Vol. 45. pp. 170–176. doi: 10.1021/BA-1964-0045.ch014 . ISBN  0-8412-0046-7 . ISSN  0065-2393 .
  3. ^ Iwamoto ET (February 1981). “Pharmacologic effects of N-allylnormetazocine (SKF-10047)”. NIDA Research Monograph . 34 : 82–8. PMID  6783955 .
  4. ^ a b Narayanan S, Bhat R, Mesangeau C, Poupaert JH, McCurdy CR (January 2011). “Early development of sigma-receptor ligands”. Future Medicinal Chemistry . 3 (1): 79–94. doi: 10.4155/fmc.10.279 . PMID  21428827 .
  5. ^ a b c d It is f g Hayashi T, Su TP (2004). “Sigma-1 receptor ligands: potential in the treatment of neuropsychiatric disorders”. CNS Drugs . 18 (5): 269–84. doi: 10.2165/00023210-200418050-00001 . PMID  15089113 . S2CID  72726251 .
  6. ^ a b c d Tam SW (February 1985). “(+)-[3H]SKF 10,047, (+)-[3H]ethylketocyclazocine, mu, kappa, delta and phencyclidine binding sites in guinea pig brain membranes”. European Journal of Pharmacology . 109 (1): 33–41. doi: 10.1016/0014-2999 (85) 90536-9 . PMID  2986989 .
  7. ^ a b c d It is Hellewell SB, Bowen WD (September 1990). “A sigma-like binding site in rat pheochromocytoma (PC12) cells: decreased affinity for (+)-benzomorphans and lower molecular weight suggest a different sigma receptor form from that of guinea pig brain”. Brain Research . 527 (2): 244–53. doi: 10.1016/0006-8993 (90) 91143-5 . PMID  2174717 . S2CID  24546226 .
  8. ^ a b Gharagozlou P, Hashemi E, Delorey TM, Clark JD, Lameh J (January 2006). “Pharmacological profiles of opioid ligands at kappa opioid receptors” . BMC Pharmacology . 6 : 3. doi: 10.1186/1471-2210-6-3 . PMC  1403760 . PMID  16433932 .
  9. ^ a b Gharagozlou P, Demirci H, David Clark J, Lameh J (January 2003). “Activity of opioid ligands in cells expressing cloned mu opioid receptors” . BMC Pharmacology . 3 : 1. doi: 10.1186/1471-2210-3-1 . PMC  140036 . PMID  12513698 .
  10. ^ a b Gharagozlou P, Demirci H, Clark JD, Lameh J (November 2002). “Activation profiles of opioid ligands in HEK cells expressing delta opioid receptors” . BMC Neuroscience . 3 : 19. doi: 10.1186/1471-2202-3-19 . PMC  137588 . PMID  12437765 .
  11. ^ a b c d It is Chou YC, Liao JF, Chang WY, Lin MF, Chen CF (March 1999). “Binding of dimemorfan to sigma-1 receptor and its anticonvulsant and locomotor effects in mice, compared with dextromethorphan and dextrorphan”. Brain Research . 821 (2): 516–9. doi: 10.1016/s0006-8993(99)01125-7 . PMID  10064839 . S2CID  22762264 .
  12. ^ Gordon M, Lafferty JJ, Tedeschi DH, Eddy NB, el (December 1961). “A new potent analgetic antagonist” . Nature . 192 (4807): 1089. Bibcode: 1961Natur.192.1089G . doi: 10.1038/1921089a0 . PMID  13900480 . S2CID  4212447 .
  13. ^ a b c d Almeida O, Shippenberg TS (6 December 2012). Neurobiology of Opioids . Springer Science & Business Media. pp. 356–. ISBN  978-3-642-46660-1 .
  14. ^ a b Schüttler J, Schwilden H (8 January 2008). Modern Anesthetics . Springer Science & Business Media. pp. 97–. ISBN  978-3-540-74806-9 .
  15. ^ Martin WR, Eades CG, Thompson JA, Huppler RE, Gilbert PE (June 1976). “The effects of morphine- and nalorphine- like drugs in the nondependent and morphine-dependent chronic spinal dog”. The Journal of Pharmacology and Experimental Therapeutics . 197 (3): 517–32. PMID  945347 .

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