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| Other names | SKF-10047; WIN-19631;N-Allylnormetazocine; NANM; NAN; ANMC; 2'-Hydroxy-5,9-dimethyl-2-allyl-6,7-benzomorphan |
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| ECHA InfoCard | 100.162.264 |
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| Formula | C17H23NO |
| Molar mass | 257.377 g·mol−1 |
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Alazocine (developmental code nameSKF-10047), also known more commonly asN-allylnormetazocine (NANM), is asyntheticopioidanalgesic of thebenzomorphan family related tometazocine, which was never marketed.[1][2][3] In addition to its opioid activity, the drug is asigma receptoragonist, and has been used widely inscientific research in studies of thisreceptor.[4][5] Alazocine is described as apotent analgesic,psychotomimetic orhallucinogen, andopioid antagonist.[2] Moreover, one of itsenantiomers was the first compound that was found toselectivelylabel theσ1 receptor, and led to the discovery and characterization of the receptor.[4][5]
Alazocine showsstereoselectivity in itspharmacodynamics.[6] The (−)-enantiomer is anon-selective and high-affinityligand of theμ-,κ-, andδ-opioid receptors (Ki = 3.0, 4.7, and 15 nM inguinea pigbrainmembranes) with very low affinity for thesigma σ1 receptor (Ki = 1,800–4,657 nM in guinea pig brain membranes).[6][7] It acts as a moderate-efficacypartial agonist of the κ-opioid receptor (Ki = 0.4 nM,EC50 = 24 nM, andEmax = 66% for (±)-alazocine against themouse receptortransfected inHEK293 cells)[8] and as anantagonist of the μ-opioid receptor (Ki = 1.15 nM for (±)-alazocine against the mouse receptor transfected in HEK293 cells).[9] It is also anagonist of the δ-opioid receptor with far lower potency (Ki = not reported,IC50 = 184 nM, andImax = 68% for (±)-alazocine against the mouse receptor transfected in HEK293 cells).[10]
Conversely, the (+)-stereoisomer has little affinity for theopioid 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-affinityagonist of the σ1 receptor (Ki = 48–66 nM in guinea pig brain membranes).[6][7] However, the (+)-enantiomer also shows moderate affinity for thedizocilpine (MK-801) orphencyclidine (PCP) site of theNMDA receptor (Ki = 587 nM inrat brain membranes relative to 45 nM for the σ1 receptor) and, hence, is anuncompetitiveNMDA 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 thesigma σ2 receptor (Ki = 13,694 nM and 4,581 nM for the (+)- and (−)-enantiomers, respectively, in rat brain membranes or ratPC12 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 inradioligand 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]
Alazocine was one of the early members of thebenzomorphan family ofopioidanalgesics to be investigated.[1] It was first described in thescientific literature in 1961.[12] Its development resulted fromnalorphine (N-allylnormorphine), a potent analgesic andopioid antagonist with similar pharmacology which had been introduced in the mid-1950s.[1] Alazocine was found to produce strongpsychotomimetic effects in humans, and it was not further developed for clinical use.[13][1] Subsequently, other benzomorphans, such aspentazocine (anN-dimethylallylbenzomorphan),cyclazocine (anN-cyclopropylmethylbenzomorphan), andphenazocine (anN-phenylethylbenzomorphan), were developed, and some have been marketed for use as analgesics.[1]
Thesigma 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 theNMDA 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 theκ-opioid receptor and/or antagonism of the NMDA receptor.[13][5] Thesigma σ2 receptor was discovered and named in 1990, and was identified in part due to the dramatically reducedaffinity of alazocine for the receptor relative to the σ1 receptor (in contrast to non-selective ligands likehaloperidol,ditolylguanidine, and(+)-3-PPP, which show similar affinity for both subtypes).[7]
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