Bioorganic & Medicinal Chemistry Letters xxx (2005) xxx–xxx 1-Pentyl-3-phenylacetylindoles, a new class of cannabimimetic John W. Huffman,a,* Paul V. Szklennik,a Amanda Almond,a Kristen Bushell,a Dana E. Selley,b Hengjun He,b Michael P. Cassidy,b Jenny L. Wileyb and Billy R. Martinb aHoward L. Hunter Laboratory, Clemson University, Clemson, SC 29634-0973, USA bDepartment of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Received 12 May 2005; revised 30 May 2005; accepted 2 June 2005 Abstract—A new class of cannabimimetic indoles, with 3-phenylacetyl or substituted 3-phenylacetyl substituents, has been preparedand their affinities for the cannabinoid CB1 and CB2 receptors have been determined. In general those compounds with a 2-substi-tuted phenylacetyl group have good affinity for both receptors. The 4-substituted analogs have little affinity for either receptor, whilethe 3-substituted compounds are intermediate in their affinities. Two of these compounds, 1-pentyl-3-(2-methylphenylacetyl)indole(JWH-251) and 1-pentyl-3-(3-methoxyphenylacetyl)indole (JWH-302), have 5-fold selectivity for the CB1 receptor with modest affin-ity for the CB2 receptor. GTPcS determinations indicate that both compounds are highly efficacious agonists at the CB1 receptorand partial agonists at the CB2 receptor.
Ó 2005 Published by Elsevier Ltd.
In the classical investigation of the structure–activity hydro-1-naphthoyl) compound had moderate affinity relationships (SAR) of cannabimimetic aminoalkyl- for the CB1 receptor and was quite potent in inhibiting indoles, such as WIN-55,212-2 (1), it was found that a the electrically induced contractions of the isolated 3-(1-naphthoyl) substituent appended to the indole mouse vas deferens. The compound with a 3-(5,6,7,8-tet- nucleus provided greater affinity for the cannabinoid rahydro-1-naphthoyl) substituent had considerably less CB1 receptor than a substituted benzoyl group.Nearly affinity for the receptor, but was slightly more potent simultaneously, we demonstrated that the N-aminoalkyl than the 1,2,3,4-tetrahydro-1-naphthoyl analog in the group could be replaced by an alkyl group without loss mouse vas deferens protocol. It was suggested that the of cannabinoid activity. An n-pentyl group on the indole potency of these compounds is due to the presence of nitrogen, as in JWH-018 (2), provided maximum affinity a bicyclic substituent at C-3 of the indole, rather than for the CB1 receptor, and in vivo potency typical of tra- to specific aromatic interactions. However, there now ditional cannabinoids, such as D9-tetrahydrocannabinol exists convincing evidence that cannabimimetic indoles, (3, D9-THCSubsequently, we prepared a number of including aminoalkylindoles, interact with the CB1 N-alkyl 3-(1-naphthoyl)indole derivatives to develop receptor primarily by aromatic stacking.
SAR for cannabimimetic indoles at both the CB1 andCB2 receptors.
There appeared to be two plausible explanations forthe greatly enhanced CB1 receptor affinities of the 3- Among the compounds included in the study by (1-naphthoyl)indoles. Either the presence of a second the Winthrop group were aminoalkylindoles with aromatic ring increased the magnitude of stacking inter- 3-(1,2,3,4-tetrahydro-1-naphthoyl) and 3-(5,6,7,8-tetra- actions with the CB1 receptor or the geometry of the hydro-1-naphthoyl) substituents.The 3-(1,2,3,4-tetra- naphthoyl indoles is such that the second aromatic ring(carbons 5–8) is proximate to aromatic amino acids inthe receptor, which would increase the stacking interac- Keywords: Cannabinoids; Structure–activity relationships; Cannabi- tions. To gain evidence regarding this question, we pre- pared a series of 1-pentyl-3-phenylacetylindoles (4, * Corresponding author. Tel.: +1 86 4656 3133; fax: +1 86 4656 These indole derivatives include compounds 0960-894X/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2005.06.008 J. W. Huffman et al. / Bioorg. Med. Chem. Lett. xxx (2005) xxx–xxx both with and without a C-2 methyl substituent (4, R = CH3 or H). A variety of compounds were synthe- sized, including those with methyl-, methoxy-, fluoro-,chloro-, and bromophenyl substituents as well as the The 3-(2-substituted phenylacetyl)indoles have good to high affinity for the CB1 receptor. The highest affinitycompounds are 1-pentyl-3-(2-chlorophenylacetyl)indole Cannabimimetic indoles were synthesized from 1- (JWH-203), with Ki = 8.0 ± 0.9 nM and 1-pentyl-3- pentylindole (5, R = H) or 2-methyl-1-pentylindole (5, R = CH3) and the appropriate phenylacetyl chloride by the Okauchi modification of the Friedel–Crafts reac- tyl)indole (JWH-306), the 1-pentyl-3-(2-fluoropheny- tion (In this procedure the substrate in- lacetyl)indoles (JWH-311 and JWH-314), and the 1- dole is stirred in dichloromethane with 1.5 equiv of pentyl-3-(2-methylphenylacetyl)indoles (JWH-251 and dimethylaluminum chloride at 0 °C for up to 1 h. To this JWH-252) have the lowest affinities of this group of intermediate organoaluminum compound is added compounds with Ki = 23–39 nM. The other 3-(2-substi- 1.5 equiv of the acyl halide.Evidence for the forma- tuted phenylacetyl)indoles, JWH-204, JWH-305, and tion of an organoaluminum intermediate follows from the observation that reaction of 1-pentylindole withdimethylaluminum chloride and quenching with D2O Those compounds with a 3-substituted phenylacetyl group have CB1 receptor affinities intermediate betweenthose of the 2- and 4-substituted analogs. In particular, The affinities of the phenylacetylindoles for the CB1 recep- tor were determined by measuring their ability to displace [3H]CP-55,940 from its binding site in a membrane prep- tyl)indole (JWH-237, Ki = 38 ± 10 nM) have quite high aration from rat brain,and CB2 receptor affinities were affinity for the CB1 receptor. The corresponding 2- determined by measuring the ability of the compounds to methylindoles (JWH-253 and JWH-303) have significant- displace [3H]CP-55,940 from a cloned human receptor ly lower affinities than JWH-237 and JWH-302. Both 1- prepThe results of these determinations are pentyl-3-(3-fluorophenylacetyl)indole (JWH-312) and summarized in The receptor affinities for WIN- the corresponding 2-methylindole (JWH-315) have mod- 55,212-2 (1) and D9-THC (3) are also included in est and little affinity, respectively, for the CB1 receptor.
The receptor affinities summarized in indicate In general the CB2 receptor affinities of this class of in- that in general the 2-methylindoles have lower affinity doles follow the same trend as their CB1 affinities ( for the CB1 receptor than the 2-unsubstituted analogs.
That is, the 2-substituted phenylacetyl compounds This is a general trend in the cannabimimetic indole ser- have the greatest affinity, followed by the 3-substituted The compounds with an unsubstituted pheny- analogs. The 3-(4-substituted phenylacetyl)indoles have lacetyl group (JWH-167 and JWH-205) have modest negligible affinity for the CB2 receptor, and most of affinities (Ki = 90 ± 17 nM and 124 ± 23 nM, respective- the 2-methylindoles have lower CB2 receptor affinities ly) for the CB1 receptor. The 4-substituted analogs than the unsubstituted analogs. However, in the 1-pen- (JWH-208, JWH-209, JWH-201, JWH-202, JWH-313, tyl-3-(2-methylphenylacetyl)indoles the 2-methylindole JWH-316, JWH-206, JWH-207, JWH-248, and JWH- analog (JWH-252, Ki = 19 ± 1 nM) has more than 7- J. W. Huffman et al. / Bioorg. Med. Chem. Lett. xxx (2005) xxx–xxx Table 1. Receptor affinities (mean ± SEM) of 1-pentyl-3-phenylacetylindoles fold greater affinity for the CB2 receptor than the unsub- noid full agonist. JWH-251 and JWH-302 both stimu- stituted compound (JWH-251, Ki = 146 ± 36 nM) late GTPcS binding at CB1, with approximately equalvalues of EC50 (29 nM) and are high efficacy agonists In contrast to most cannabimimetic indoles, which tend with Emax of greater than 90% (Although the to show selectivity for the CB2 receptor,two of affinities of these compounds at CB2 are approximately these phenylacetylindoles show 5-fold selectivity for one-fifth that of their affinities for the CB1 receptor, the CB1 receptor. One of them, 1-pentyl-3-(2-methylph- both significantly stimulate GTPcS binding at the CB2 enylacetyl)indole, JWH-251, has good affinity for the receptor. Surprisingly, their potencies for CB2 receptor CB1 receptor (Ki = 29 ± 3 nM) with modest affinity for activation were similar to those seen with CB1: for the CB2 receptor (Ki = 146 ± 36 nM). The other, 1-pen- JWH-251, EC50 = 8.3 ± 0.8 nM and for JWH-302, tyl-3-(3-methoxyphenylacetyl)indole, JWH-302, also has EC50 = 24.4 ± 6.9 nM. At the CB2 receptor, however, good affinity (Ki = 17 ± 2 nM) for the CB1 receptor, and both compounds are partial agonists with Emax values fair affinity for the CB2 receptor (Ki = 89 ± 15 nM). To evaluate the efficacy of these compounds, their abilityto stimulate [35S]GTPcS binding at CB1 and CB2 was The 1-pentyl-3-phenylacetylindoles constitute a new determined.The results of these determinations are class of cannabimimetic indoles, which in contrast to summarized in , where the stimulation produced most compounds of this general type show little selectiv- at each receptor is normalized to a standard cannabi- ity for the CB2 receptor. Two of these indole derivatives, Table 2. EC50 and Emax values (mean ± SEM) for stimulation by GTPcS binding of CB1 and CB2 for JWH-251 and JWH-302 1-Pentyl-3-(2-methylphenylacetyl)indole (JWH-251) 1-Pentyl-3-(3-methoxyphenylacetyl)indole (JWH-302) a Stimulation values are from data normalized to stimulation produced by a maximally effective concentration of a standard full agonist: 10 lM WIN-55,212-2 for CB1 and 3 lM CP-55,940 for CB2 receptors.
J. W. Huffman et al. / Bioorg. Med. Chem. Lett. xxx (2005) xxx–xxx JWH-251 and JWH-302, are moderately selective for the 3. Wiley, J. L.; Compton, D. R.; Dai, D.; Lainton, J. A. H.; Phillips, M.; Huffman, J. W.; Martin, B. R. J. Pharmacol.
1 receptor and are full agonists at this receptor. Selec- although these compounds are also partial agonists at 4. Aung, M. M.; Griffin, G.; Huffman, J. W.; Wu, M.-J.; Keel, C.; Yang, B.; Showalter, V. M.; Abood, M. E.; 2 receptor, they may serve as the prototypes for Martin, B. R. Drug Alcohol Depend. 2000, 60, 133.
additional CB1 receptor selective agonists. In addition, 5. Huffman, J. W. Curr. Med. Chem. 1999, 6, 705.
the high CB1 receptor affinities of several of these com- 6. Huffman, J. W. Curr. Pharm. Des. 2000, 6, 1323.
pounds combined with the efficacies of JWH-251 and 7. Huffman, J. W.; Zengin, G.; Wu, M.-J.; Lu, J.; Hynd, JWH-302 suggest that the increased potency of cannab- G.; Bushell, K.; Thompson, A.; Bushell, S.; Tartal, C.; imimetic 3-(1-naphthoyl)indoles relative to their benzoyl Hurst, D. P.; Reggio, P. H.; Selley, D. E.; Cassidy, M.
congeners is caused by their molecular geometry rather P.; Wiley, J. L.; Martin, B. R. Bioorg. Med. Chem. 2005, than the presence of a second aromatic ring.
8. Reggio, P. H.; Basu-Dutt, S.; Barnett-Norris, J.; Castro, M. T.; Hurst, D. P.; Seltzman, H. H.; Roche, M. J.;Gilliam, A. F.; Thomas, B. F.; Stevenson, L. A.; Pertwee, R. G.; Abood, M. E. J. Med. Chem. 1998, 41, 5177.
9. Huffman, J. W.; Mabon, R.; Wu, M.-J.; Lu, J.; Hart, R.; The work at Clemson was supported by Grants Hurst, D. P.; Reggio, P. H.; Wiley, J. L.; Martin, B. R.
DA03590 and DA15340 to J.W.H., that at Virginia Commonwealth University by Grant DA03672 to 10. Okauchi, T.; Itonaga, M.; Minami, T.; Owa, T.; Kitoh, B.R.M. and DA05274 to D.E.S., all from the National K.; Yoshino, H. Org. Lett. 2000, 2, 1485.
11. The phenylacetyl indoles were formed in unoptimized yields of 32–72%. All target compounds have massspectral, 1H, and 13C NMR data consistent with theassigned structures. All compounds gave acceptable microanalytical or high-resolution mass spectral data.
12. Compton, D. R.; Rice, K. C.; De Costa, B. R.; Razdan, 1. Eissenstat, M. A.; Bell, M. R.; DÕAmbra, T. E.; Alexander, R. K.; Melvin, L. S.; Johnson, M. R.; Martin, B. R.
E. J.; Daum, S. J.; Ackerman, J. H.; Gruett, M. D.; Kumar, J. Pharmacol. Exp. Ther. 1993, 265, 218.
V.; Estep, K. G.; Olefirowicz, E. M.; Wetzel, J. R.; 13. Showalter, V. M.; Compton, D. R.; Martin, B. R.; Abood, Alexander, M. D.; Weaver, J. D.; Haycock, D. A.; Luttin- M. E. J. Pharmacol. Exp. Ther. 1996, 278, 989.
ger, D. A.; Casiano, F. M.; Chippari, S. M.; Kuster, J. E.; 14. Selley, D. E.; Stark, S.; Sim, L. J.; Childers, S. R. Life Sci.
Stevenson, J. I.; Ward, S. J. J. Med. Chem. 1995, 38, 3094.
1996, 59, 659, Chinese hamster ovary (CHO) cells stably 2. Huffman, J. W.; Dai, D.; Martin, B. R.; Compton, D. R.
expressing the human CB1 or CB2 receptor were employed Bioorg. Med. Chem. Lett. 1994, 4, 563.


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