3496 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 22
Communications to the Editor
social interaction test in the rat at doses (0.1-1 mg/kg
ip) similar to those that antagonized mCPP-induced
hypolocomotion, with no evidence of sedative effects.4
Significantly, 5 showed no evidence of either procon-
vulsant (up to 30 mg/kg po) or hyperphagic properties
which are characteristic of mutant mice lacking the
5-HT2C receptor.12 Thus, 5 is the first reported brain
penetrant 5-HT2C receptor antagonist able to discrimi-
nate between 5-HT2C and 5-HT2B components of central
activity.13 The detailed in vivo properties of 5 are the
subject of a separate publication.4
Refer en ces
(1) (a) Hoyer, D.; Clarke, D. E.; Fozard, J . R.; Hartig, P. R.; Martin,
G. R.; Mylecharane, E. J .; Saxena, P. R.; Humphrey, P. P. A.
International Union of Pharmacology Classification of Receptors
for 5-Hydroxytryptamine. Pharmacol. Rev. 1994, 46, 157-203.
(b) Baxter, G.; Kennett, G. A.; Blaney, F.; Blackburn, T. 5-HT2
Receptor Subtypes: A Family Re-united? Trends Pharmacol.
Sci. 1995, 16, 105-110.
(2) (a) Kahn, R. S.; Wetzler, S. mCPP as a Probe of Serotonin
Function. Biol. Psychiat. 1991, 30, 1139-1166. (b) Kennett,
G. A. 5-HT1C receptors and their therapeutic relevance. Curr.
Opin. Invest. Drugs 1993, 2, 317-362 and references therein.
(c) Kennett, G. A.; Pittaway, K.; Blackburn, T. P. Evidence that
5-HT1C Receptor Antagonists are Anxiolytic in the Geller-Seifter
Model of Anxiety. Psychopharmacology 1994, 114, 90-96.
(3) Forbes, I. T.; Ham, P.; Booth, D. H.; Martin, R. T.; Thompson,
M.; Baxter, G. S.; Blackburn, T. P.; Glen, A.; Kennett, G. A.;
Wood, M. D. 5-Methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetra-
Dock in g of 5 in to th e 5-HT2C Recep tor . The
bipyridyl ether 5 was manually docked into a model of
the 5-HT2C receptor, constructed on the basis of the
structure of bacteriorhodopsin as we have previously
described,7 and the ligand-receptor complex was mini-
mized using the CHARMm program14 (Figure 1). The
proposed binding mode is similar to that previously
proposed6 for 1 with the urea carbonyl oxygen double
hydrogen bonding to the hydroxyl side chains of Ser312
and Ser315.15 In addition, the indole NH of Trp613 is
also in a position to hydrogen bond to the urea carbonyl.
The central pyridyl ring occupies a lipophilic pocket
surrounded by Phe508 and Phe616, while the terminal
pyridyl ring occupies another lipophilic pocket formed
by Ile305 and Ile410. In this mode it is possible that
the terminal pyridyl nitrogen is hydrogen bonding to
Ser413. This ligand receptor interaction cannot be
invoked in the case of the 5-HT2B receptor as the
corresponding residue in the protein sequence is ala-
nine, and this difference may contribute to the observed
selectivity. The substituted indoline is placed in an-
other pocket, the boundary of which is defined by
residues Val212, Val608, Met612, and Tyr715. In the
5-HT2B receptor the corresponding 608 residue is leu-
cine, and in the 5-HT2A receptor both the 212 and 608
residues are leucine. These differences would be ex-
pected to lead to binding pockets of reduced size, and it
is proposed that these steric differences in the receptors
may also account for the observed 5-HT2C selectivity.
In summary, we report the synthesis and biological
activity of substituted 1-(3-pyridylcarbamoyl)indolines
which illustrates the use of 5,6-disubstitution as a
replacement for a fused 5-membered ring in the context
of 5-HT2C/2B receptor antagonists. Although compounds
such as 3 and 4 were found to be potent and selective
5-HT2C/2B receptor antagonists, they were also very
potent inhibitors of a number of human cytochrome
P450 enzymes which precluded their development as
potential anxiolytic agents. Elaboration of the left hand
side pyridyl ring abolished the inhibitory activity,
leading to bipyridyl ethers such as 5, which is the first
reported brain penetrant, 5-HT2C receptor antagonist
with selectivity over both the 5-HT2A and 5-HT2B recep-
tor subtypes. Furthermore, 5 was found to exert
marked anxiolytic-like responses in rat models, confirm-
ing that these responses are mediated by 5-HT2C recep-
tor blockade.
hydropyrrolo[2,3-f]indole:
Antagonist with Improved Affinity, Selectivity and Oral Activity.
J . Med. Chem. 1995, 38, 2524-2530.
A Novel 5-HT2C/5-HT2B Receptor
(4) Kennett, G. A.; Wood, M. D.; Bright, F.; Trail, B.; Riley, G.;
Holland, V.; Avenell, K. Y.; Stean, T.; Upton, N.; Bromidge, S.
M.; Forbes, I. T.; Brown, A. M.; Middlemiss, D. N.; Blackburn,
T. P. SB-242084, A Selective and Brain Penetrant 5-HT2C
Receptor Antagonist. Neuropharmacology 1997, 36, 609-620.
(5) Kennett, G. A.; Wood, M. D.; Bright, F.; Cilia, J .; Piper, D. C.;
Gager, T.; Thomas, D.; Baxter, G. S.; Forbes, I. T.; Ham, P.;
Blackburn, T. P. In Vitro and In Vivo Profile of SB-206553, A
Potent 5-HT2C/5-HT2B Receptor Antagonist with Anxiolytic-like
Properties. Br. J . Pharmacol. 1996, 117, 427-434.
(6) Unpublished results from the Department of Drug Metabolism
and Pharmacokinetics, SmithKline Beecham.
(7) Forbes, I. T.; Dabbs, S.; Duckworth, D. M.; Ham, P.; J ones, G.
E.; King, F. D.; Saunders, D. V.; Blaney, F. E.; Naylor, C. B.;
Baxter, G. S.; Blackburn, T. P.; Kennett, G. A.; Wood, M. D.
Synthesis, Biological Activity and Molecular Modelling Studies
of Selective 5-HT2C/2B Receptor Antagonists. J . Med. Chem.
1996, 39, 4966-4977.
(8) Ham, P.; J ones, G. E.; Forbes, I. T. WO Patent 95/01976,
published 19 J anuary 1995.
(9) Lewis, D. F. V. Cytochromes P450: Structure, Function and
Mechanism; Taylor and Francis Publishing: 1996.
(10) Gaster, L. M.; Wyman, P. A.; Mulholland, K. R.; Davies, D. T.;
Duckworth, D. M.; Forbes, I. T.; J ones, G. E. WO Patent 96/23,-
783, published 8 August 1996.
(11) Reifschneider, W.; Kelyman, J . S. US Patent 3,406,202, pub-
lished 15 October 1968.
(12) Tecott, L. H.; Sun, L. M.; Akana, S. F.; Strack, A. M.; Dallman,
M. F.; J ulius, D. Eating disorder and epilepsy in mice lacking
5-HT2C serotonin receptors. Nature 1995, 374, 542-546.
(13) A series of benzenesulfonamido-hydantoins which are claimed
to be 5-HT
2C receptor antagonists with additional selectivity over
the 5-HT2B receptor subtype has recently been reported. Wein-
hardt, K. K.; Bonhaus, D. W.; De Souza, A. Some Benzene-
sulfonamido-Substituted Valerophenones That are Selective
Antagonists for the 5-HT2C Receptor. Bioorg. Med. Chem. Lett.
1996, 6, 2687-2692. However, in the light of a report detailing
the pharmacology of one of these compounds that concludes that
its CNS distribution “may be restricted to areas where the
blood-brain barrier is not fully intact”, it seems very unlikely
that these highly polar compounds are brain penetrant. Bon-
haus, D. W.; Weinhardt, K. K.; Taylor, M.; Desouza, A.; McNee-
ley, P. M.; Szczepanski, K.; Fontana, D. J .; Trinh, J .; Rocha, C.
L.; Dawson, M. W.; Flippin, L. A.; Eglen, R. M. RS-102221: A
Novel High Affinity and Selective, 5-HT2C Receptor Antagonist.
Neuropharmacology 1997, 36, 621-629.
(14) Brooks, B. R.; Bruccoleri, R. E.; Olafson, B. D.; States, D. J .;
Swaminathan, S.; Karplus, M. CHARMM. A Program for
Macromolecular Energy, Minimization and Dynamics Calcula-
tions. J . Comput. Chem. 1983, 4, 187-217.
(15) The naming convention used here is that the first number refers
to the helix and the next two numbers refer to the position in
that helix. Thus Ser312 is the twelfth residue in helix 3.
(16) Baldwin, S. J .; Bloomer, J . C.; Smith, G. J .; Ayrton, A. D.; Clarke,
S. E.; Chenery, R. J . Ketoconazole and Sulfaphenazole as the
respective selective inhibitors of P453A and 2C9. Xenobiotica
1995, 25, 261-270.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for the synthesis of 2-5 (8 pages). Ordering information
is given on any current masthead page.
J M970424C