Aminoalkylindoles, cannabinoid

Xie X-Q, Eissentat M, Makriyannis A. Common cannabimimetic phar-macophoric requirements between aminoalkylindoles and classical cannabinoids. Life Sci 1995 56 1963-1970. 

Jansen EM, Haycock DA, Ward SJ, Seybold VS. Distribution of cannabinoid receptors in rat brain determined with aminoalkylindoles. Brain Res 1992 575 93-102. 

Besides the classical cannabinoids there are other structural classes with cannabinoid activity the non-classical cannabinoids typified by CP-55,940 and the aminoalkylindols exemplified with WIN 55,212-2. The 1H-pyrazole-3-carboxylic acid amide derivatives SR 141716A (Rinaldi-Carmona et al., 1994) and SR 144528 (Rinaldi-Carmona et al., 1998) were discovered to be moderately selective cannabinoid receptor antagonists. 

The first identified cannabinoid receptor subtype, CB was cloned and demonstrated to have an amino acid sequence consistent with a tertiary structure typical of the seven transmembrane-spanning proteins that are coupled to G proteins. In addition to being found in the central nervous system, mRNA for CB has also been identified in testes. The central nervous system responses to cannabinoid compounds are believed to be mediated exclusively by CB, inasmuch as CB2 transcripts could not be found in brain tissue by either Northern analysis or in situ hybridization studies. CBj transduces signals in response to central-nervous-system-active constituents of C. sativa as well as synthetic bicyclic and tricyclic cannabinoid analogs, aminoalkylindole, and eicosanoid cannabimimetic compounds. CB is coupled to G, to inhibit adenylate cyclase activity and to a pertussis-sensitive G protein to regulate Ca2+ currents. 

A second antagonist, AM 630 (24b), a novel aminoalkylindole, was found to attenuate the ability of some cannabinoids to inhibit electrically-evoked twitches of the mouse isolated vas deferens [114]. AM 630 was a more potent antagonist of d9-THC than of anandamide (Kd of 14.0 and 278.8 nM, respectively). It was suggested that the receptors for which AM 630 has the highest activity may not be CB, cannabinoid receptors. This is supported by the observation that AM 630 is actually a cannabinoid agonist in the myenteric plexus - muscle preparation [115]. Yamada et al. [116] showed that isothiocyanate derivatives of pravadoline can serve as potential electrophilic affinity ligands for CB],... 

In terms of chemical structure, established cannabinoid receptor agonists fall essentially into four main groups classical, nonclassical, aminoalkylindole and eicosanoid (reviewed in Howlett et al. 2002 Pertwee 1999a). 

Members of the eicosanoid group of cannabinoid receptor agonists have markedly different structures both from the aminoalkylindoles and from classical and nonclassical cannabinoids. Important members of this group are the endocannabinoids, arachidonoylethanolamide (anandamide), 0-arachidonoylethan-olamine (virodhamine), 2-arachidonoyl glycerol and 2-arachidonyl glyceryl... 

One recently developed synthetic cannabinoid receptor agonist that interacts almost as well with CB2 as with CBi receptors (Tables 1 and 2) is BAY 38-7271 (De Vry and Jentzsch 2002 Mauler et al. 2002, 2003). This compound has a structure that is not classical, non-classical, aminoalkylindole or eicosanoid (Fig. 9). 

The best CB2-selective agonists to have been developed to date are all non-eicosanoid cannabinoids (Howlett et al. 2002 Ibrahim et al. 2003 Pertwee 1999a). They include the classical cannabinoids, L-759633, L-759656 and JWH-133, the non-classical cannabinoid HU-308, and the aminoalkylindole AM1241 (Figs. 5,6 and 7). All these ligands bind more readily to CB2 than to CBi receptors (Table 2) and have also been shown to behave as potent CB2-selective agonists in functional bioassays (Hanus et al. 1999 Ibrahim et al. 2003 Pertwee 2000 Ross et al. 1999a). 

Keywords Adenylyl cyclase Aminoalkylindole Anandamide Ca Cannabinoid Cyclic AMP Depolarization suppression of inhibition or excitation Desensitization Endocannabinoid G proteins Ion channels Mitogen activated protein kinases Neurotransmission Nitric oxide Serine/threonine kinases Seven-transmembrane spanning receptors Synaptic plasticity Tyrosine kinases... 

Chin C, Murphy J, Huffman J, Kendall D (1999) The third transmembrane helix of the cannabinoid receptor plays a role in the selectivity of aminoalkylindoles for CB2, peripheral cannabinoid receptor. J Pharmacol Exp Ther 291 837-844... 

Eissenstat MA, Bell MR, D Ambra TE, Alexander EJ, Daum SJ, Ackerman JH, Gruett MD, Kumar V, Estep KG, Olefirowicz EM, et al (1995) Aminoalkylindoles structure-activity relationships of novel cannabinoid mimetics. J Med Chem 38 3094-3105... 

D Ambra TE, Eissenstat MA, Abt J, Ackerman JH, Bacon ER, BeU MR, Carabateas PM, Josef KA, Kumar V, Weaver JDl, Arnold R, Casiano FM, Chippari SM, Haycock DA, Kuster JE, Luttinger DA, Stevenson LA, Ward SJ, HiU WA, Khanolkar AD, Makriyannis A (1996) C-attached aminoalkylindoles potent cannabinoid mimetics. Bioorg Med Chem Lett 6 17-22... 

Reggio PH, Basu-Dutt S, Barnett-Norris J, Castro MT, Hurst DP, Seltzman HH, Roche MJ, GUliam AF, Thomas BF, Stevenson LA, Pertwee RG, Abood ME (1998) The bioactive conformation of aminoalkylindoles at the cannabinoid CBl and CB2 receptors insights gained from (E)- and (Z)-naphthylidene indenes. J Med Chem 41 5177-5187... 

Ward SJ, Baizman E, Bell M, Childers S, D Ambra T, Eissenstat M, Estep K, Haycock D, Howlett A, Luttinger D, et al (1991) Aminoalkylindoles (AAIs) a new route to the cannabinoid receptor NIDA Res Monogr 105 425-426... 

Fig. 1. Representative structures ofthe different cannabinoid receptor ligand classes the plant cannabinoid, A -tetrahydrocannabinol the endocannabinoid, arachidonoyl ethanolamide (anandamide) the synthetic pyrazole inverse agonist AM281 and the potent aminoalkylindole agonist AM2233. Both AM281 and AM2233 contain an iodine atom that has been labeled with radioiodine for in vitro and in vivo binding experiments...

The cannabinoid ligand can be classified according to Ooms et al [43] into six groups i) classical, ii) nonclassical, iii) bicyclic, iv) aminoalkylindoles, v) endocannabinoid analogues, vi) diarylpyrazoles. Ooms et al [43] studied the pharmacophore of 3-alkyl-5-arylimidazolidinediones as a new CBi cannabinoid receptor. Thomas et al [44] have studied SAR data on a series of 1,5-diphenylpyrazoles proposing a pharmacophoric alignment of these compounds with THC... 

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