Contents

Alazocine

Alazocine

Clinical data
Other names	SKF-10047; WIN-19631; N-Allylnormetazocine; NANM; NAN; ANMC; 2'-Hydroxy-5,9-dimethyl-2-allyl-6,7-benzomorphan
ATC code	None
Identifiers
IUPAC name (±)-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 Y 34061-23-9 (hydrochloride) 14198-28-8 ((−)-isomer) 58640-82-7 ((+)-isomer) 74957-58-7 ((−)-isomer HCl) 133005-41-1 ((+)-isomer HCl)
PubChem CID	1235
ChemSpider	1198 Y
UNII	L884482HDD
ChEMBL	ChEMBL274099 Y
CompTox Dashboard (EPA)	DTXSID20931281
ECHA InfoCard	100.162.264
Chemical and physical data
Formula	C17H23NO
Molar mass	257.377 g·mol−1
3D model (JSmol)	Interactive image
SMILES CC1C2CC3=C(C1(CCN2CC=C)C)C=C(C=C3)O
InChI 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 Y Key:LGQCVMYAEFTEFN-UHFFFAOYSA-N Y
NY (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, psychotomimeticorhallucinogen, 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]

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 σ₁ 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, EC₅₀ = 24 nM, and E_max = 66% for (±)-alazocine against the mouse receptor transfectedinHEK293 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, IC₅₀ = 184 nM, and I_max = 68% for (±)-alazocine against the mouse receptor transfected in HEK293 cells).^[10]

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 σ₁ 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 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 (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 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[edit]

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 (anN-dimethylallylbenzomorphan), cyclazocine (anN-cyclopropylmethylbenzomorphan), and phenazocine (anN-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]

References[edit]