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Revision as of 05:03, 17 February 2012 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Saving copy of the {{drugbox}} taken from revid 474385568 of page Alazocine for the Chem/Drugbox validation project (updated: 'CAS_number').		Latest revision as of 18:36, 21 October 2024 edit JWBE (talk | contribs)Extended confirmed users10,127 edits removed Category:Phenols; added Category:Hydroxyarenes using HotCat
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			{{Short description|Synthetic opioid analgesic}}
	{{ambox | text = This page contains a copy of the infobox ({{tl|drugbox}}) taken from revid of page ] with values updated to verified values.}}
			{{Distinguish|N-Allylnormorphine}}
	{{Drugbox		{{Drugbox
	| Verifiedfields = changed		| Verifiedfields = changed
			| Watchedfields = changed
	| verifiedrevid = 456676945		| verifiedrevid = 477316370
	| IUPAC_name = (2''R'',6''R'',11''R'')- 6,11-dimethyl- 3-prop- 2-en- 1-yl- 1,2,3,4,5,6-hexahydro- 2,6-methano- 3-benzazocin- 8-ol		| IUPAC_name = (±)-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(2-propen-1-yl)-2,6-methano-3-benzazocin-8-ol
	| image = Allylnormetazocine.svg		| image = Alazocine.svg
			| width = 185px
	<!--Clinical data-->		<!--Clinical data-->
	| tradename =		| tradename =
	| pregnancy_category =		| pregnancy_category =
	| legal_status = Uncontrolled		| legal_status =
	| routes_of_administration = ?		| routes_of_administration =
	<!--Pharmacokinetic data-->		<!--Pharmacokinetic data-->
	| bioavailability =		| bioavailability =
	| metabolism =		| metabolism =
	| elimination_half-life =		| elimination_half-life =
	| excretion =		| excretion =
	<!--Identifiers-->		<!--Identifiers-->
	| CAS_number_Ref = {{cascite|changed|??}}		| CAS_number_Ref = {{cascite|correct|CAS}}
	| CAS_number = <!-- blanked - oldvalue: 14198-28-8 -->		| CAS_number = 825594-24-9
			| UNII_Ref = {{fdacite|correct|FDA}}
⚫	| ATC_prefix = none
			| UNII = L884482HDD
⚫	| ATC_suffix =
			| CAS_supplemental = <br />34061-23-9 (])<br />14198-28-8 ((−)-isomer)<br />58640-82-7 ((+)-isomer)<br />74957-58-7 ((−)-isomer {{abbr|HCl|hydrochloride}})<br />133005-41-1 ((+)-isomer {{abbr|HCl|hydrochloride}})
		⚫	| ATC_prefix = None
		⚫	| ATC_suffix =
	| ChEMBL_Ref = {{ebicite|correct|EBI}}		| ChEMBL_Ref = {{ebicite|correct|EBI}}
	| ChEMBL = 330376		| ChEMBL = 274099
	| PubChem = 3036246		| PubChem = 1235
	| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}		| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
	| ChemSpiderID = 2300306		| ChemSpiderID = 1198
			| synonyms = SKF-10047; WIN-19631; ''N''-Allylnormetazocine; NANM; NAN; ANMC; 2'-Hydroxy-5,9-dimethyl-2-allyl-6,7-benzomorphan
	<!--Chemical data-->		<!--Chemical data-->
	| C=17 | H=23 | N=1 | O=1		| C=17 | H=23 | N=1 | O=1
		⚫	| SMILES = CC1C2CC3=C(C1(CCN2CC=C)C)C=C(C=C3)O
	| molecular_weight = 257.37 g/mol
⚫	| smiles = C12CC3=C(1(CCN2CC=C)C)C=C(C=C3)O
	| InChI = 1/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/t12-,16+,17+/m0/s1
	| InChIKey = LGQCVMYAEFTEFN-JCURWCKSBW
	| StdInChI_Ref = {{stdinchicite|correct|chemspider}}		| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
	| StdInChI = 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/t12-,16+,17+/m0/s1		| StdInChI = 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
	| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}		| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
	| StdInChIKey = LGQCVMYAEFTEFN-JCURWCKSSA-N		| StdInChIKey = LGQCVMYAEFTEFN-UHFFFAOYSA-N
	}}		}}
			'''Alazocine''' (developmental code name '''{{abbr|SKF|Smith, Kline & French}}-10047'''), also known more commonly as '''''N''-allylnormetazocine''' ('''NANM'''), is a ] ] ] of the ] family related to ], which was never marketed.<ref name="CasyParfitt2013">{{cite book| vauthors = Casy AF, Parfitt RT |title=Opioid Analgesics: Chemistry and Receptors|url=https://books.google.com/books?id=vwAHCAAAQBAJ&pg=PA176|date=29 June 2013|publisher=Springer Science & Business Media|isbn=978-1-4899-0585-7|pages=176–178, 420–421}}</ref><ref name="KeatsTelford1964">{{cite book| vauthors = Keats AS, Telford J |title=Molecular Modification in ''Drug'' Design|chapter=Narcotic Antagonists as Analgesics|series=Advances in Chemistry|volume=45|year=1964|pages=170–176|issn=0065-2393|doi=10.1021/ba-1964-0045.ch014|isbn=0-8412-0046-7}}</ref><ref name="pmid6783955">{{cite journal | vauthors = Iwamoto ET | title = Pharmacologic effects of N-allylnormetazocine (SKF-10047) | journal = NIDA Research Monograph | volume = 34 | pages = 82–8 | date = February 1981 | pmid = 6783955 }}</ref> In addition to its opioid activity, the drug is a ] ], and has been used widely in ] in studies of this receptor.<ref name="pmid21428827">{{cite journal | vauthors = Narayanan S, Bhat R, Mesangeau C, Poupaert JH, McCurdy CR | title = Early development of sigma-receptor ligands | journal = Future Medicinal Chemistry | volume = 3 | issue = 1 | pages = 79–94 | date = January 2011 | pmid = 21428827 | doi = 10.4155/fmc.10.279 }}</ref><ref name="pmid15089113">{{cite journal | vauthors = Hayashi T, Su TP | title = Sigma-1 receptor ligands: potential in the treatment of neuropsychiatric disorders | journal = CNS Drugs | volume = 18 | issue = 5 | pages = 269–84 | year = 2004 | pmid = 15089113 | doi = 10.2165/00023210-200418050-00001 | s2cid = 72726251 }}</ref> Alazocine is described as a ] analgesic, ] or ], and ].<ref name="KeatsTelford1964" /> Moreover, one of its ]s was the first compound that was found to ] ] the ], and led to the discovery and characterization of the receptor.<ref name="pmid21428827" /><ref name="pmid15089113" />
			==Pharmacology==
			===Pharmacodynamics===
			Alazocine shows ] in its ].<ref name="pmid2986989">{{cite journal | vauthors = Tam SW | title = (+)-SKF 10,047, (+)-ethylketocyclazocine, mu, kappa, delta and phencyclidine binding sites in guinea pig brain membranes | journal = European Journal of Pharmacology | volume = 109 | issue = 1 | pages = 33–41 | date = February 1985 | pmid = 2986989 | doi = 10.1016/0014-2999(85)90536-9 }}</ref> The (−)-enantiomer is a non-selective and high-] ] of the ], ], and ]s (K<sub>i</sub> = 3.0, 4.7, and 15&nbsp;nM in ] ] ]) with very low affinity for the sigma σ<sub>1</sub> receptor (K<sub>i</sub> = 1,800–4,657&nbsp;nM in guinea pig brain membranes).<ref name="pmid2986989" /><ref name="pmid2174717" /> It acts as a moderate-] ] of the κ-opioid receptor (K<sub>i</sub> = 0.4&nbsp;nM, ] = 24&nbsp;nM, and ] = 66% for (±)-alazocine against the ] receptor ] in ] cells)<ref name="pmid16433932">{{cite journal | vauthors = Gharagozlou P, Hashemi E, DeLorey TM, Clark JD, Lameh J | title = Pharmacological profiles of opioid ligands at kappa opioid receptors | journal = BMC Pharmacology | volume = 6 | pages = 3 | date = January 2006 | pmid = 16433932 | pmc = 1403760 | doi = 10.1186/1471-2210-6-3 | doi-access = free }}</ref> and as an ] of the μ-opioid receptor (K<sub>i</sub> = 1.15&nbsp;nM for (±)-alazocine against the mouse receptor transfected in HEK293 cells).<ref name="pmid12513698">{{cite journal | vauthors = Gharagozlou P, Demirci H, David Clark J, Lameh J | title = Activity of opioid ligands in cells expressing cloned mu opioid receptors | journal = BMC Pharmacology | volume = 3 | pages = 1 | date = January 2003 | pmid = 12513698 | pmc = 140036 | doi = 10.1186/1471-2210-3-1 | doi-access = free }}</ref> It is also an ] of the δ-opioid receptor with far lower potency (K<sub>i</sub> = not reported, ] = 184&nbsp;nM, and {{abbr|I<sub>max</sub>|maximal inhibition}} = 68% for (±)-alazocine against the mouse receptor transfected in HEK293 cells).<ref name="pmid12437765">{{cite journal | vauthors = Gharagozlou P, Demirci H, Clark JD, Lameh J | title = Activation profiles of opioid ligands in HEK cells expressing delta opioid receptors | journal = BMC Neuroscience | volume = 3 | pages = 19 | date = November 2002 | pmid = 12437765 | pmc = 137588 | doi = 10.1186/1471-2202-3-19 | doi-access = free }}</ref>
			Conversely, the (+)-] has little affinity for the ]s (K<sub>i</sub> for 1,900&nbsp;nM, 1,600&nbsp;nM, and 19,000&nbsp;nM for the μ-, κ-, δ-opioid receptors in guinea pig brain membranes) and instead is a selective and high-affinity ] of the σ<sub>1</sub> receptor (K<sub>i</sub> = 48–66&nbsp;nM in guinea pig brain membranes).<ref name="pmid2986989" /><ref name="pmid2174717" /> However, the (+)-enantiomer also shows moderate affinity for the ] (MK-801) or ] (PCP) site of the ] (K<sub>i</sub> = 587&nbsp;nM in ] brain membranes relative to 45&nbsp;nM for the σ<sub>1</sub> receptor) and, hence, is an ] ] as well at higher concentrations.<ref name="pmid10064839">{{cite journal | vauthors = Chou YC, Liao JF, Chang WY, Lin MF, Chen CF | title = Binding of dimemorfan to sigma-1 receptor and its anticonvulsant and locomotor effects in mice, compared with dextromethorphan and dextrorphan | journal = Brain Research | volume = 821 | issue = 2 | pages = 516–9 | date = March 1999 | pmid = 10064839 | doi = 10.1016/s0006-8993(99)01125-7 | s2cid = 22762264 }}</ref> As such, (+)-alazocine is only modestly selective as a ligand of the σ<sub>1</sub> receptor.<ref name="pmid10064839" />
			Both enantiomers of alazocine have very low affinity for the sigma ] (K<sub>i</sub> = 13,694&nbsp;nM and 4,581&nbsp;nM for the (+)- and (−)-enantiomers, respectively, in rat brain membranes or rat ] cells).<ref name="pmid10064839" /><ref name="pmid2174717" /><ref name="pmid15089113" /> As such, due to its high affinity for the σ<sub>1</sub> receptor, (+)-alazocine can be used to distinguish between the two sigma receptor subtypes in scientific research, for instance in ]s.<ref name="pmid10064839" /><ref name="pmid15089113" />
			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<ref name="pmid16433932" /><ref name="pmid12513698" /><ref name="pmid12437765" /> with very low affinity for the sigma receptors, while (+)-alazocine is a selective agonist of the sigma σ<sub>1</sub> receptor and to a lesser (~10-fold) extent antagonist of the NMDA receptor with low affinity for the opioid and sigma σ<sub>2</sub> receptors.<ref name="pmid2986989" /><ref name="pmid2174717" /><ref name="pmid10064839" /><ref name="pmid15089113" />
			==History==
			Alazocine was one of the early members of the ] family of opioid analgesics to be investigated.<ref name="CasyParfitt2013" /> It was first described in the ] in 1961.<ref name="pmid13900480">{{cite journal | vauthors = Gordon M, Lafferty JJ, Tedeschi DH, Eddy NB, May EL | title = A new potent analgetic antagonist | journal = Nature | volume = 192 | issue = 4807 | pages = 1089 | date = December 1961 | pmid = 13900480 | doi = 10.1038/1921089a0 | bibcode = 1961Natur.192.1089G | s2cid = 4212447 | doi-access = free }}</ref> Its development resulted from ] (N-allylnormorphine), a potent analgesic and opioid antagonist with similar pharmacology which had been introduced in the mid-1950s.<ref name="CasyParfitt2013" /> Alazocine was found to produce strong psychotomimetic effects in humans, and it was not further developed for clinical use.<ref name="AlmeidaShippenberg2012" /><ref name="CasyParfitt2013" /> Subsequently, other benzomorphans, such as ] (an ''N''-dimethylallylbenzomorphan), ] (an ''N''-cyclopropylmethylbenzomorphan), and ] (an ''N''-phenylethylbenzomorphan), were developed, and some have been marketed for use as analgesics.<ref name="CasyParfitt2013" />
			The sigma σ<sub>1</sub> receptor was named in 1976 and (+)-alazocine was described as its prototypical ligand.<ref name="AlmeidaShippenberg2012">{{cite book| vauthors = Almeida O, Shippenberg TS |title=Neurobiology of Opioids|url=https://books.google.com/books?id=PmH7CAAAQBAJ&pg=PA356|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-46660-1|pages=356–}}</ref><ref name="SchüttlerSchwilden2008">{{cite book| vauthors = Schüttler J, Schwilden H |title=Modern Anesthetics|url=https://books.google.com/books?id=JpkkWhPbh2QC&pg=PA97|date=8 January 2008|publisher=Springer Science & Business Media|isbn=978-3-540-74806-9|pages=97–}}</ref><ref name="pmid945347">{{cite journal | vauthors = Martin WR, Eades CG, Thompson JA, Huppler RE, Gilbert PE | title = The effects of morphine- and nalorphine- like drugs in the nondependent and morphine-dependent chronic spinal dog | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 197 | issue = 3 | pages = 517–32 | date = June 1976 | pmid = 945347 }}</ref> 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.<ref name="AlmeidaShippenberg2012" /><ref name="SchüttlerSchwilden2008" /><ref name="pmid15089113" /> The psychotomimetic effects of alazocine and the other benzomorphans were initially attributed incorrectly to agonism of the σ<sub>1</sub> 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.<ref name="AlmeidaShippenberg2012" /><ref name="pmid15089113" /> The sigma σ<sub>2</sub> 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<sub>1</sub> receptor (in contrast to non-selective ligands like ], ], and ], which show similar affinity for both subtypes).<ref name="pmid2174717">{{cite journal | vauthors = Hellewell SB, Bowen WD | title = 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 | journal = Brain Research | volume = 527 | issue = 2 | pages = 244–53 | date = September 1990 | pmid = 2174717 | doi = 10.1016/0006-8993(90)91143-5 | s2cid = 24546226 }}</ref>
			== References ==
			{{Reflist|2}}
			{{Hallucinogens}}
			{{Ionotropic glutamate receptor modulators}}
			{{Opioid receptor modulators}}
			{{Sigma receptor modulators}}
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