A. Coop et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2449±2451
2451
Table 2. Antinociceptive activity of 5 and 6 in the mousea
sc mg/kgb
References and Notes
1. Portoghese, P. S.; Sultana, M.; Takemori, A. E. J. Med.
Chem. 1990, 33, 1714.
TFc
TF vs Md
PPQe
HPf
2. Dondio, G.; Ronzoni, S.; Petrillo, P. Exp. Opin. Ther.
Patents 1999, 9, 353.
3. Menkens, K.; Bilsky, E. J.; Wild, K. D.; Portoghese, P. S.;
Reid, L. D.; Porreca, F. Eur. J. Pharmacol. 1992, 219, 345.
4. Suzuki, T.; Mori, T.; Tsuji, M.; Misawa, M.; Nagase, H.
Life Sci. 1994, 55, PL339.
5. June, H. L.; McCane, S. R.; Zink, R. W.; Portoghese, P. S.;
Li, T. K.; Froehlich, J. C. Psychopharmacology 1999, 147, 81.
6. House, R. V.; Thomas, P. T.; Kozak, J. T.; Bhargava, H.
N. Neurosci. Lett. 1995, 198, 119.
7. Abdelhamid, E. E.; Sultana, M.; Portoghese, P. S.; Take-
mori, A. E. J. Pharmacol. Exp. Ther. 1991, 258, 299.
8. Schiller, P. W.; Fundytus, M. E.; Merovitz, L.; Wel-
trowska, G.; Nguyen, T. M. D.; Lemieux, C.; Chung, N. N.;
Coderre, T. J. J. Med. Chem. 1999, 42, 3520.
5 (Cyclohexylmethyl) Inactive
6 (Cyclohexylethyl)
Inactive
Ð
Inactive
0.39
(0.17±0.86) (1.57±3.73)
Inactive
2.42
3.86
(2.66±5.59)g
a3 was inactive in all mouse assays.16 `Inactive' is stated when less than
half of the mice were aected at 30 mg/kg.
bParenthesized numbers represent 95% con®dence limits.
cTail ¯ick: morphine sulfate=0.73 (0.35±1.53).
dTail ¯ick vs morphine: naloxone=0.04 (0.01±0.09).
eParaphenylquinone: morphine sulfate=0.4 (0.2±0.8).
fHot plate: morphine sulfate=3.1 (1.5±6.4).
gNaloxone AD50=0.1 (0.07±0.6), b-FNA (mg/brain) AD50=1.25
(0.51±3.07), norBNI Inactive, naltrindole Inactive.
9. Ananthan, S.; Kezar, H. S.; Carter, R. L.; Saini, S. K.; Rice,
K. C.; Wells, J. L.; Davis, P.; Xu, H.; Dersch, C. M.; Bilsky, E. J.;
Porreca, F.; Rothman, R. B. J. Med. Chem. 1999, 42, 3527.
10. Dondio, G.; Ronzoni, S.; Petrillo, P. Exp. Opin. Ther.
Patents 1997, 7, 1075.
11. Takemori, A. E.; Sultana, M.; Nagase, H.; Portoghese,
P. S. Life Sci. 1992, 50, 1491.
12. Portoghese, P. S.; Sultana, M.; Moe, S. T.; Takemori,
A. E. J. Med. Chem. 1994, 37, 579.
being equipotent with morphine in the hot plate and
antiwrithing, but ®vefold less potent than morphine in
the tail ¯ick. The potent antinociceptive activity in the
hot plate, coupled with the potent reversal of the anti-
nociception seen in the tail ¯ick by the m preferring
antagonist naloxone, strongly suggests the antinociceptive
eects to be m-mediated. This pro®le was con®rmed by
the reversal of the antinociception in the tail ¯ick by a
selective m antagonist (b-FNA), but not by a k or d
antagonist (norBNI and naltrindole, respectively).
13. Coop, A.; Rothman, R. B.; Dersch, C.; Partilla, J.;
Porreca, F.; Davis, P.; Jacobson, A. E.; Rice, K. C. J. Med.
Chem. 1999, 42, 1673.
14. Coop, A.; Pinto, J.; Wang, L.; McCullough, K.; Roth-
man, R. B.; Dersch, C.; Jacobson, A. E.; Rice, K. C. Bioorg.
Med. Chem. Lett. 1999, 9, 3435.
15. Maguire, P. A.; Perez, J. J.; Tsai, N. F.; Rodriguez, L.;
Beatty, M. F.; Villar, H. O.; Kamal, J. J.; Upton, C.; Casy,
A. F.; Loew, G. H. Mol. Pharmacol. 1993, 44, 1246.
16. May, E. L.; Jacobson, A. E.; Mattson, M. V.; Coop, A.;
Aceto, M. D.; Bowman, E. R.; Traynor, J. R.; Woods, J. H.;
Harris, L. S. Med. Chem. Res. 1998, 8, 311.
17. Casy, A. F.; Par®tt, R. T. Opioid Analgesics; Plenum: New
York and London, 1986.
18. Portoghese, P. S.; Larson, D. L.; Sultana, M.; Takemori,
A. E. J. Med. Chem. 1992, 35, 4325.
This work shows that there is little dierence between a
saturated ring and an aromatic ring one carbon
removed from the nitrogen, but there are dierences
when the ring is two carbons distant. Importantly, the
N-cyclohexylethyl substituted indolomorphinan pos-
sesses a pro®le of m preferring agonism, and suggests
that ligands with a pro®le of m agonism and d antagon-
ism can be developed in this series of ligands. Further
studies to fully characterize the pharmacological pro®le
of this unique ligand are currently underway.
19. Olofson, R. A.; Martz, J. T.; Senet, J.-P.; Piteau, M.;
Malfroot, T. J. Org. Chem. 1984, 49, 2081.
Acknowledgement
20. Spectra were consistent with the assigned structures; the
salts gave satisfactory microanalyses (Æ0.4%).
The authors wish to thank Mallinckrodt for the gener-
ous gift of oxycodone.
21. Emmerson, P. J.; Liu, M. R.; Woods, J. H.; Medzih-
radsky, F. J. Pharmacol. Exp. Ther. 1994, 271, 1630.