title: The synthesis and pharmacological evaluation of adamantane-derived indoles: cannabimimetic drugs of abuse.
abstract: Two novel adamantane derivatives, adamantan-1-yl(1-pentyl-1H-indol-3-yl)methanone (AB-001) and N-(adamtan-1-yl)-1-pentyl-1H-indole-3-carboxamide (SDB-001), were recently identified as cannabimimetic indoles of abuse. Conflicting anecdotal reports of the psychoactivity of AB-001 in humans, and a complete dearth of information about the bioactivity of SDB-001, prompted the preparation of AB-001, SDB-001, and several analogues intended to explore preliminary structure-activity relationships within this class. This study sought to elucidate which structural features of AB-001, SDB-001, and their analogues govern the cannabimimetic potency of these chemotypes in vitro and in vivo. All compounds showed similar full agonist profiles at CB1 (EC50 = 16-43 nM) and CB2 (EC50 = 29-216 nM) receptors in vitro using a FLIPR membrane potential assay, with the exception of SDB-002, which demonstrated partial agonist activity at CB2 receptors. The activity of AB-001, AB-002, and SDB-001 in rats was compared to that of Δ(9)-tetrahydrocannabinol (Δ(9)-THC) and cannabimimetic indole JWH-018 using biotelemetry. SDB-001 dose-dependently induced hypothermia and reduced heart rate (maximal dose 10 mg/kg) with potency comparable to that of Δ(9)-tetrahydrocannabinol (Δ(9)-THC, maximal dose 10 mg/kg), and lower than that of JWH-018 (maximal dose 3 mg/kg). Additionally, the changes in body temperature and heart rate affected by SDB-001 are of longer duration than those of Δ(9)-THC or JWH-018, suggesting a different pharmacokinetic profile. In contrast, AB-001, and its homologue, AB-002, did not produce significant hypothermic and bradycardic effects, even at relatively higher doses (up to 30 mg/kg), indicating greatly reduced potency compared to Δ(9)-THC, JWH-018, and SDB-001.
authors.affiliation: School of Chemistry, The University of Sydney, NSW 2006, Australia.
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Banister
authors.forename: Shane M
authors.initials: SM
authors.lastname: Wilkinson
authors.forename: Mitchell
authors.initials: M
authors.lastname: Longworth
authors.forename: Jordyn
authors.initials: J
authors.lastname: Stuart
authors.forename: Nadine
authors.initials: N
authors.lastname: Apetz
authors.forename: Katrina
authors.initials: K
authors.lastname: English
authors.forename: Lance
authors.initials: L
authors.lastname: Brooker
authors.forename: Catrin
authors.initials: C
authors.lastname: Goebel
authors.forename: David E
authors.initials: DE
authors.lastname: Hibbs
authors.forename: Michelle
authors.initials: M
authors.lastname: Glass
authors.forename: Mark
authors.initials: M
authors.lastname: Connor
authors.forename: Iain S
authors.initials: IS
authors.lastname: McGregor
authors.forename: Michael
authors.initials: M
authors.lastname: Kassiou
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002186:Cannabinoids / Q000493:pharmacokinetics; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology*; D051379:Mice; D051381:Rats
chemical_list: C576035:3-((adamantan-1-yl)carbonyl)-1-pentylindole; D002186:Cannabinoids; D007211:Indoles; C584513:N-(adamtan-1-yl)-1-pentyl-1H-indole-3-carboxamide; D000218:Adamantane
references.citation: J Neuroendocrinol. 2008 May;20 Suppl 1:10-4
references.pmid: 18426493
references.citation: Drug Test Anal. 2012 Jun;4(6):519-24
references.pmid: 22102533
references.citation: Pediatrics. 2011 Dec;128(6):e1622-7
references.pmid: 22065271
references.citation: Drug Alcohol Depend. 2011 Sep 1;117(2-3):152-7
references.pmid: 21316162
references.citation: Biochem Pharmacol. 2012 Apr 1;83(7):952-61
references.pmid: 22266354
references.citation: J Mass Spectrom. 2012 Jul;47(7):825-35
references.pmid: 22791249
references.citation: Resuscitation. 2012 Sep;83(9):1145-51
references.pmid: 22289684
references.citation: J Mass Spectrom. 2009 May;44(5):832-7
references.pmid: 19189348
references.citation: Drug Alcohol Depend. 2012 Jun 1;123(1-3):148-53
references.pmid: 22127210
references.citation: Brain Res. 2008 Sep 4;1228:145-60
references.pmid: 18619424
references.citation: Forensic Sci Int. 2013 Apr 10;227(1-3):21-32
references.pmid: 23063179
references.citation: Toxicol Lett. 2010 Sep 1;197(3):157-62
references.pmid: 20566335
references.citation: J Pharmacol Exp Ther. 1998 Jun;285(3):995-1004
references.pmid: 9618400
references.citation: Front Behav Neurosci. 2011 Sep 21;5:60
references.pmid: 22007163
references.citation: Braz J Psychiatry. 2006 Jun;28(2):153-7
references.pmid: 16810401
references.citation: Drug Alcohol Rev. 2013 Mar;32(2):141-6
references.pmid: 23043552
references.citation: J Emerg Med. 2013 Feb;44(2):360-6
references.pmid: 22989695
references.citation: Forensic Sci Int. 2012 Jan 10;214(1-3):27-32
references.pmid: 21813254
references.citation: Pharmacology. 1977;15(1):63-72
references.pmid: 14347
references.citation: Eur J Med Chem. 2011 Oct;46(10):5086-98
references.pmid: 21885167
references.citation: Org Lett. 2000 May 18;2(10):1485-7
references.pmid: 10814479
references.citation: J Med Chem. 2010 Jan 14;53(1):295-315
references.pmid: 19921781
references.citation: Forensic Sci Int. 2009 Oct 30;191(1-3):58-63
references.pmid: 19589652
references.citation: J Med Chem. 1992 Jan;35(1):124-35
references.pmid: 1732519
references.citation: Forensic Sci Int. 2012 Feb 10;215(1-3):8-13
references.pmid: 21546175
references.citation: J Mass Spectrom. 2012 Jan;47(1):54-65
references.pmid: 22282090
references.citation: Annu Rev Pharmacol Toxicol. 2006;46:101-22
references.pmid: 16402900
references.citation: Drug Alcohol Depend. 2000 Aug 1;60(2):133-40
references.pmid: 10940540
references.citation: Br J Pharmacol. 1978 Jun;63(2):267-73
references.pmid: 667419
references.citation: J Pediatr Pharmacol Ther. 2012 Apr;17(2):177-81
references.pmid: 23118671
references.citation: PLoS One. 2011;6(7):e21917
references.pmid: 21755008
references.citation: J Mass Spectrom. 2010 Oct;45(10):1186-94
references.pmid: 20857386
references.citation: J Anal Toxicol. 2010 Jun;34(5):252-60
references.pmid: 20529459
references.citation: J Biomol Screen. 2013 Mar;18(3):269-76
references.pmid: 23015017
references.citation: Ann Pharmacother. 2011 Mar;45(3):414-7
references.pmid: 21325097
references.citation: Am J Emerg Med. 2012 Sep;30(7):1320.e5-7
references.pmid: 21802885
references.citation: J Neurosci. 1995 Oct;15(10):6552-61
references.pmid: 7472417
references.citation: Chem Pharm Bull (Tokyo). 2011;59(9):1203-5
references.pmid: 21881274
references.citation: J Med Toxicol. 2012 Mar;8(1):62-4
references.pmid: 22160733
references.citation: Curr Opin Pharmacol. 2006 Dec;6(6):586-91
references.pmid: 17027338
references.citation: Br J Pharmacol. 2008 Jan;153(2):319-34
references.pmid: 17994113
references.citation: J Pharm Pharmacol. 2009 Jul;61(7):839-53
references.pmid: 19589225
references.citation: J Mass Spectrom. 2012 Feb;47(2):195-200
references.pmid: 22359329
references.citation: Expert Opin Pharmacother. 2010 Jan;11(1):17-31
references.pmid: 20001426
references.citation: Expert Opin Emerg Drugs. 2009 Mar;14(1):43-65
references.pmid: 19249987
references.citation: J Pharmacol Exp Ther. 1982 Nov;223(2):516-23
references.pmid: 6290642
references.citation: AAPS J. 2005 Oct 24;7(3):E625-54
references.pmid: 16353941
references.citation: Psychopharmacology (Berl). 2012 Mar;220(2):417-26
references.pmid: 21989802
references.citation: Forensic Sci Int. 2011 May 20;208(1-3):e31-5
references.pmid: 21482054
references.citation: Aust N Z J Psychiatry. 2012 Mar;46(3):281-2
references.pmid: 22391292
references.citation: Pharmacol Rev. 2002 Jun;54(2):161-202
references.pmid: 12037135
references.citation: J Emerg Med. 2011 Mar;40(3):296-9
references.pmid: 21167669
references.citation: Addiction. 2010 Oct;105(10):1859-60
references.pmid: 20840203
references.citation: Acta Crystallogr A. 2008 Jan;64(Pt 1):112-22
references.pmid: 18156677
references.citation: Cleve Clin J Med. 2012 Apr;79(4):258-64
references.pmid: 22473725
references.citation: Clin Toxicol (Phila). 2011 Oct;49(8):760-4
references.pmid: 21970775
references.citation: Bioorg Med Chem Lett. 2010 Nov 15;20(22):6721-4
references.pmid: 20855210
references.citation: J Med Chem. 2011 Aug 11;54(15):5444-53
references.pmid: 21702498
references.citation: Pharmacol Rev. 2010 Dec;62(4):588-631
references.pmid: 21079038
references.citation: Clin Toxicol (Phila). 2011 Jun;49(5):431-3
references.pmid: 21740143
references.citation: Forensic Sci Med Pathol. 2006 Mar;2(1):13-8
references.pmid: 25868498
references.citation: J Med Chem. 2012 Jun 14;55(11):5391-402
references.pmid: 22548457
references.citation: Chem Res Toxicol. 2012 Apr 16;25(4):825-7
references.pmid: 22404317