Alazocine

Last updated
Alazocine
Alazocine.svg
Clinical data
Other namesSKF-10047; WIN-19631; N-Allylnormetazocine; NANM; NAN; ANMC; 2'-Hydroxy-5,9-dimethyl-2-allyl-6,7-benzomorphan
ATC code
  • None
Identifiers
  • (±)-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  Yes check.svgY
    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
UNII
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.162.264 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C17H23NO
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 Yes check.svgY
  • Key:LGQCVMYAEFTEFN-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Alazocine (developmental code name SKF-10047), also known more commonly as N-allylnormetazocine (NANM), is a synthetic opioid analgesic of the benzomorphan family related to metazocine, which was never marketed. [1] [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 σ1 receptor, and led to the discovery and characterization of the receptor. [4] [5]

Contents

Pharmacology

Pharmacodynamics

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 (Ki = 3.0, 4.7, and 15 nM in guinea pig brain membranes) with very low affinity for the sigma σ1 receptor (Ki = 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 (Ki = 0.4 nM, EC50 = 24 nM, and Emax = 66% for (±)-alazocine against the mouse receptor transfected in HEK293 cells) [8] and as an antagonist of the μ-opioid receptor (Ki = 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 (Ki = not reported, IC50 = 184 nM, and Imax = 68% for (±)-alazocine against the mouse receptor transfected in HEK293 cells). [10]

Conversely, the (+)-stereoisomer has little affinity for the opioid receptors (Ki 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 σ1 receptor (Ki = 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 (Ki = 587 nM in rat brain membranes relative to 45 nM for the σ1 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 σ1 receptor. [11]

Both enantiomers of alazocine have very low affinity for the sigma σ2 receptor (Ki = 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 σ1 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] [10] with very low affinity for the sigma receptors, while (+)-alazocine is a selective agonist of the sigma σ1 receptor and to a lesser (~10-fold) extent antagonist of the NMDA receptor with low affinity for the opioid and sigma σ2 receptors. [6] [7] [11] [5]

History

Alazocine was one of the early members of the benzomorphan family of opioid analgesics to be investigated. [1] It was first described in the scientific literature in 1961. [12] Its development resulted from nalorphine (N-allylnormorphine), a potent analgesic and opioid antagonist with similar pharmacology which had been introduced in the mid-1950s. [1] Alazocine was found to produce strong psychotomimetic effects in humans, and it was not further developed for clinical use. [13] [1] 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. [1]

The sigma σ1 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 σ1 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 σ2 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 σ1 receptor (in contrast to non-selective ligands like haloperidol, ditolylguanidine, and (+)-3-PPP, which show similar affinity for both subtypes). [7]

Related Research Articles

Agonist Chemical which binds to and activates a biochemical receptor

An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the agonist, while an inverse agonist causes an action opposite to that of the agonist.

Opioid receptor Group of biological receptors

Opioid receptors are a group of inhibitory G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostatin receptors (SSTRs). Opioid receptors are distributed widely in the brain, in the spinal cord, on peripheral neurons, and digestive tract.

Sigma receptors (σ-receptors) are protein cell surface receptors that bind ligands such as 4-PPBP, SA 4503 (cutamesine), ditolylguanidine, dimethyltryptamine, and siramesine. There are two subtypes, sigma-1 receptors (σ1) and sigma-2 receptors (σ2), which are classified as sigma receptors for their pharmacological similarities, even though they are evolutionarily unrelated.

κ-opioid receptor Protein-coding gene in the species Homo sapiens

The κ-opioid receptor or kappa opioid receptor, abbreviated KOR or KOP, is a G protein-coupled receptor that in humans is encoded by the OPRK1 gene. The KOR is coupled to the G protein Gi/G0 and is one of four related receptors that bind opioid-like compounds in the brain and are responsible for mediating the effects of these compounds. These effects include altering nociception, consciousness, motor control, and mood. Dysregulation of this receptor system has been implicated in alcohol and drug addiction.

BIMU8

BIMU-8 is a drug which acts as a 5-HT4 receptor selective agonist. BIMU-8 was one of the first compounds of this class. The main action of BIMU-8 is to increase the rate of respiration by activating an area of the brain stem known as the pre-Botzinger complex.

Sigma-1 receptor

The sigma-1 receptor (σ1R), one of two sigma receptor subtypes, is a chaperone protein at the endoplasmic reticulum (ER) that modulates calcium signaling through the IP3 receptor. In humans, the σ1 receptor is encoded by the SIGMAR1 gene.

Nociceptin receptor

The nociceptin opioid peptide receptor (NOP), also known as the nociceptin/orphanin FQ (N/OFQ) receptor or kappa-type 3 opioid receptor, is a protein that in humans is encoded by the OPRL1 gene. The nociceptin receptor is a member of the opioid subfamily of G protein-coupled receptors whose natural ligand is the 17 amino acid neuropeptide known as nociceptin (N/OFQ). This receptor is involved in the regulation of numerous brain activities, particularly instinctive and emotional behaviors. Antagonists targeting NOP are under investigation for their role as treatments for depression and Parkinson's disease, whereas NOP agonists have been shown to act as powerful, non-addictive painkillers in non-human primates.

Diprenorphine

Diprenorphine, also known as diprenorfin, is a non-selective, high-affinity, weak partial agonist of the μ- (MOR), κ- (KOR), and δ-opioid receptor (DOR) which is used in veterinary medicine as an opioid antagonist. It is used to reverse the effects of super-potent opioid analgesics such as etorphine and carfentanil that are used for tranquilizing large animals. The drug is not approved for use in humans.

Siramesine

Siramesine is a sigma receptor agonist, selective for the σ2 subtype. In animal studies, siramesine has been shown to produce anxiolytic and antidepressanteffects. It was developed by the pharmaceutical company H Lundbeck for the treatment of anxiety, although development was discontinued after clinical trials showed a lack of efficacy in humans.

Sigma-2 receptor

The sigma-2 receptor (σ2R) is a sigma receptor subtype that has attracted attention due to its involvement in diseases such as cancer and neurological diseases. It is currently under investigation for its potential diagnostic and therapeutic uses.

Nalorphine Chemical compound

Nalorphine (INN), also known as N-allylnormorphine, is a mixed opioid agonist–antagonist with opioid antagonist and analgesic properties. It was introduced in 1954 and was used as an antidote to reverse opioid overdose and in a challenge test to determine opioid dependence.

Dezocine Opioid analgesic

Dezocine, sold under the brand name Dalgan, is an atypical opioid analgesic which is used in the treatment of pain. It is used by intravenous infusion and intramuscular injection.

Metazocine Opioid analgesic

Metazocine is an opioid analgesic related to pentazocine. While metazocine has significant analgesic effects, mediated through a mixed agonist–antagonist action at the mu opioid receptor, its clinical use is limited by dysphoric and hallucinogenic effects which are most likely caused by activity at kappa opioid receptors and/or sigma receptors.

Herkinorin

Herkinorin is an opioid analgesic that is an analogue of the natural product salvinorin A. It was discovered in 2005 during structure-activity relationship studies into neoclerodane diterpenes, the family of chemical compounds of which salvinorin A is a member.

Xorphanol Opioid analgesic

Xorphanol (INN), also known as xorphanol mesylate (USAN), is an opioid analgesic of the morphinan family that was never marketed.

Agonist-antagonist

In pharmacology the term agonist-antagonist or mixed agonist/antagonist is used to refer to a drug which under some conditions behaves as an agonist while under other conditions, behaves as an antagonist.

Dextrallorphan Chemical compound

Dextrallorphan (DXA) is an opioid derivative chemical of the morphinan class that is used in scientific research. It acts as a σ1 receptor agonist and NMDA receptor antagonist. It has no significant affinity for the σ2, μ-opioid, or δ-opioid receptor, or for the serotonin or norepinephrine transporter. As an NMDA receptor antagonist, in vivo, it is approximately twice as potent as dextromethorphan, and five-fold less potent than dextrorphan.

Quadazocine Chemical compound

Quadazocine (WIN-44,441) is an opioid antagonist of the benzomorphan family which is used in scientific research. It acts as a silent antagonist at all three of the major opioid receptors—μ, κ, and δ, but with a significant preference in affinity for the μ receptor and the κ2 subtype. As such, it has been touted as a "κ2-selective" antagonist, though this is not entirely accurate on account of its similar affinity for the μ receptor. As would be expected, quadazocine reverses the effects of opioid agonists like morphine and fentanyl in animals.

Thienorphine Chemical compound

Thienorphine is a very potent, extremely long-acting, orally-active opioid analgesic with mixed agonist–antagonist properties which was developed by the Beijing Institute of Pharmacology and Toxicology as a potential treatment for opioid dependence. It is a high-affinity, balanced ligand of the μ-, δ-, and κ-opioid receptors, behaving as a partial agonist of the μ- and κ-opioid receptors and as an antagonist of the δ-opioid receptor. It also possesses relatively low affinity for the nociceptin receptor, where it acts as an antagonist.

3-PPP Chemical compound

3-PPP (N-n-propyl-3-(3-hydroxyphenyl)piperidine) is a mixed sigma σ1 and σ2 receptor agonist (with similar affinity for both subtypes, though slightly higher affinity for the latter) and D2 receptor partial agonist which is used in scientific research. It shows stereoselectivity in its pharmacodynamics. (+)-3-PPP is the enantiomer that acts as an agonist of the sigma receptors; it is also an agonist of both D2 presynaptic and postsynaptic receptors. Conversely, (–)-3-PPP, also known as preclamol (INN), acts as an agonist of presynaptic D2 receptors but as an antagonist of postsynaptic D2 receptors, and has antipsychotic effects. 3-PPP has also been reported to be a monoamine reuptake inhibitor and possibly to act at adrenergic receptors or some other non-sigma receptor.

References

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  2. 1 2 Keats, Arthur S.; Telford, Jane (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. 1 2 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.
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  6. 1 2 3 4 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. 1 2 3 4 5 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.
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  11. 1 2 3 4 5 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, May EL (December 1961). "A new potent analgetic antagonist". Nature. 192 (4807): 1089. Bibcode:1961Natur.192.1089G. doi: 10.1038/1921089a0 . PMID   13900480. S2CID   4212447.
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  14. 1 2 Jürgen Schüttler; Helmut Schwilden (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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