Benzylimidazolines as Serotonin Receptor Ligands
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 13 2251
(2) Zifa, E.; Fillion, G. 5-Hydroxytryptamine receptors. Pharmacol.
Rev. 1992, 44, 401-458.
(22) Hjeds, H.; Hauser, K. P.; J ersey, B. Oximes, O-methyloximes,
and N-methyloximes of 2,6-dimethyl-4-halogenobenzaldehyde.
Acta Chem. Scand. 1985, 19, 2166-2174.
(23) Foehlisch, B.; Herrscher, O. Base catalyzed rearrangements of
3,9-dioxatricyclo[3.3.1.02,4]nonan-7-ones to form hydroxyphenyl-
carbonyl compounds. Tetrahedron 1985, 41, 1979-1983.
(24) Mandell, L.; Caine, D.; Kilpatrick, G. E. The synthesis of
dienones related to santonin and santonine via aryl participa-
tion. J . Am. Chem. Soc. 1961, 83, 4457-4460.
(25) Schubert, W. M.; Donohue, J .; Gardner, J . D. Aromatic electro-
philic substitution by hydrogen. V. The mechanism of the acid-
catalyzed decarboxylation of aromatic acids. J . Am. Chem. Soc.
1954, 76, 9-15.
(26) Glennon, R. A.; Ismaiel, A. M.; Chaurasia, C.; Titeler, M. 5-HT1D
serotonin receptors: Results of a structure-affinity investigation.
Drug Dev. Res. 1991, 22, 25-36.
(27) Ruffolo, R. R.; Rosing, E. L.; Waddell, J . E. Receptor interactions
of imidazolines. I. Affinity and efficacy for alpha adrenergic
receptors in rat aorta. J . Pharmacol. Exp. Ther. 1979, 209, 429-
436.
(28) Ruffolo, R. R.; Dillard, R. D.; Waddell, J . E.; Yaden, E. L.
Receptor interactions of imidazolines. III. Structure-activity
relationships governing alpha adrenergic receptor occupation
and receptor activation for mono- and dimethoxy-substituted
tolazoline derivatives in rat aorta. J . Pharmacol. Exp. Ther.
1979, 211, 733-738.
(29) Ghose, S.; Dattagupta, J . K. Structure of xylometazoline (otrivin)
hydrochloride, an R-adrenergic agonist. Acta Crystallogr. 1986,
C42, 1524-1526.
(30) Kaumann, A. J .; Frenken, M.; Posival, H.; Brown, A. M. Variable
participation of 5-HT1-like receptors and 5-HT2 receptors in
serotonin-induced contraction of isolated coronary arteries.
Circulation 1994, 90, 1141-1153.
(3) Martin, G. R.; Humphrey, P. P. A. Receptors for 5-hydroxy-
tryptamine: Current perspectives on classification and nomen-
clature. Neuropharmacology 1994, 33, 261-273.
(4) Boess, F. G.; Martin, I. L. Molecular biology of 5-HT receptors.
Neuropharmacology 1994, 33, 275-317.
(5) 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 (serotonin). Pharmacol. Rev. 1994, 46,
157-203.
(6) Glennon, R. A.; Dukat, M. Serotonin receptor subtypes. In
Psychopharmacology: The Fourth Generation of Progress; Bloom,
R. E., Kupfer, D. J ., Eds.; Raven Press: New York, 1994; pp 415-
429.
(7) Glennon, R. A.; Westkaemper, R. B. 5-HT1D receptors: A sero-
tonin receptor population for the 1990s. Drug News Perspect.
1993, 6, 390-405.
(8) (a) Weinshank, R. L.; Zgombick, J . M.; Macchi, M. J .; Branchek,
T.; Hartig, P. R. Human serotonin 1D receptor is encoded by a
subfamily to two distinct genes: 5-HT1DR and5-HT1Dâ. Proc. Natl.
Acad. Sci. U.S.A. 1992, 89, 3630-3634. (b) Adham, N.; Ro-
manienko, P.; Hartig, P.; Weinshank, R. L.; Branchek, T. The
rat 5-HT1B receptor is the species homologue of the human
5-hydroxytryptamine-1Dâ receptor. Mol. Pharmacol. 1992, 41,
1-7.
(9) Hamblin, M. W.; Metcalf, M. A. Primary structure and functional
characterization of a human 5-HT1D-type serotonin receptor. Mol.
Pharmacol. 1991, 40, 143-148.
(10) Demchyshyn, L.; Sunahara, R. K.; Miller, K.; Teitler, M.;
Hoffman, B. J .; Kennedy, J . L.; Seeman, P.; van Tol, H. H. M.;
Niznik, H. B. A human serotonin 1D receptor variant (5-HT1Dâ
)
encoded by an intronless gene on chromosome 6. Proc. Natl.
Acad. Sci. U.S.A. 1992, 89, 5522-5526.
(11) J in, H.; Oksenberg, D.; Ashkenazi, A.; Peroutka, S. J .; Duncan,
A. M. V.; Rozmahel, R.; Yang, Y.; Mengod, G.; Palacios, J . M.;
O’Dowd, B. F. Characterization of the human 5-hydroxytryp-
tamine-1B receptor. J . Biol. Chem. 1992, 267, 5735-5738.
(12) Levy, F. O.; Gudermann, T.; Perez-Reyes, E.; Birnbaumer, M.;
Kaumann, A. J .; Birnbaumer, L. Molecular cloning of a human
serotonin receptor (S12) with a pharmacological profile resem-
bling that of the 5-HT1D subtype. J . Biol. Chem. 1992, 267,
7553-7562.
(13) (a) Hartig, P. R.; Hoyer, D.; Humphrey, P. P. A.; Martin, G.
Alignment of receptor nomenclature with the human genome:
Classification of 5-HT1B and 5-HT1D receptor subtypes. Trends
Pharmacol. Sci. 1996, 17, 103-105. (b) Voight, M. Sibling
rivalry: the 5-HT1B/5-HT1D receptors. Invest. Drugs Res. Alerts
1997, 2, 47-51.
(14) Hamel, E. 5-HT1D receptors: Pharmacology and therapeutic
potential. Invest. Drugs Res. Alerts 1996, 1, 19-29.
(15) Dukat, M. Drug evaluation: Alniditan. Invest. Drugs Res. Alerts
1997, 2, 173-175.
(16) Clitherow, J . W.; Scopes, D. I. C.; Skingle, M.; J ordan, C. C.;
Feniuk, W.; Campbell, I. B.; Carter, M. C.; Collington, E. W.;
Connor, H. E.; Higgins, G. A.; Beattie, D.; Kelly, H. A.; Mitchell,
W. L.; Oxford, A. W.; Wadsworth, A. H.; Tyers, M. B. Evolution
of a novel series of [(N,N-dimethylamino)propyl]- and piperazi-
nylbenzanilides as the first selective 5-HT1D antagonists. J . Med.
Chem. 1994, 37, 2253-2257.
(17) Sonesson, C.; Barf, T.; Nilsson, J .; Dijkstra, D.; Carlsson, A.;
Svensson, K.; Smith, C.; Martin, I. J .; Duncan, J . N.; King, L.
J .; Wikstrom, H. Synthesis and evaluation of pharmacological
and pharmacokinetic properties of monopropyl analogues of 5-,
7-, and 8-[[(trifluoromethyl)sulfonyl]oxy]-2-aminotetralins: Cen-
tral dopamine and serotonin receptor activity. J . Med. Chem.
1995, 38, 1319-1329.
(18) Bylund, D. B.; Eikenberg, D. C.; Hieble, J . P.; Langer, S. Z.;
Lefkowitz, R. J .; Minneman, K. P.; Molinoff, P. B.; Ruffolo, R.
R.; Trendelenburg, U. International Union of Pharmacology
nomenclature of adrenoceptors. Pharmacol. Rev. 1994, 46, 121-
136.
(31) J en, T.; Van Hoeven, H.; Groves, W.; McLean, R. A.; Loev, B.
Amidines and related compounds. Studies on structure-activity
relationships of antihypertensive and antisecretory agents
related to clonidine. J . Med. Chem. 1975, 18, 90-99.
(32) Ruffalo, R. R.; Dillard, R. D.; Yaden, E. L.; Waddell, J . E.
Receptor interactions of imidazolines. II. Affinities and efficacies
of hydroxy-substituted tolazoline derivatives in rat aorta. J .
Pharmacol. Exp. Ther. 1979, 211, 74-79.
(33) Wellcome Foundation Ltd., Netherland Patent 6,508,754; J an
10, 1966.
(34) Cavallini, G.; Milla, E.; Grumelli, E.; Massarani, E.; Nardi, D.
Substituted 2-benzylimidazoline derivatives of pharmacological
activity. Farmaco Ed. Sci. 1956, 11, 633-661.
(35) Slavica, M.; Lei, L.; Patil, P. N.; Kenezy, A.; Feller, D. R.; Miller,
D. D. Synthesis and biological activities of a new set of irrevers-
ibly acting 2-(4-isothiocyanotobenzyl)imidazoline analogues in
rat thoracic aorta. J . Med. Chem. 1994, 37, 1874-1881.
(36) Nightingale, D.; J anes, J . R. The alkylation of o- and p-xylene.
J . Am. Chem. Soc. 1944, 66, 154-155.
(37) Hoi, B.; Cagniant, P. Cleavage and migrations of tertiary butyl
radicals in the course of chemical reactions. II. 1,3-Dimethyl-5-
tert-butylbenzene and its derivatives. Bull. Soc. Chim. Fr. 1942,
9, 889-892.
(38) ω-Phenylalkylamines. E. Merck A.-G., Belgian Patent 632,969,
Nov 29, 1963; Chem. Abstr. 1964, 60, 13181.
(39) Substituted amines. E. Merck A.-G., Belgian Patent 633,799, Dec
19, 1963; Chem. Abstr. 1965, 61, 4264.
(40) Glennon, R. A.; Hong, S.-S.; Bondarev, M.; Law, H.; Dukat, M.;
Rakhit, S.; Power, P.; Fan, E.; Kamboj, R.; Teitler, M.; Herrick-
Davis, K.; Smith, C. Binding of O-alkyl derivatives of serotonin
at human 5-HT1Dâ receptors. J . Med. Chem. 1996, 39, 314-322.
(41) Ismaiel, A. M.; Dukat, M.; Law, H.; Kamboj, R.; Fan, E.; Lee, D.
K. H.; Mazzocco, L.; Buekschkens, D.; Teitler, M.; Pierson, M.
E.; Glennon, R. A. 2-(1-Naphthyloxy)ethylamines with enhanced
affinity for human 5-HT1Dâ (h5-HT1B) serotonin receptors. J .
Med. Chem. 1997, 40, 4415-4419.
(42) Razzaque, Z. Differences in the effects of ketanserin and GR
127935 on 5-HT receptor-mediated responses in rat saphenous
vein and guinea pig jugular vein. Eur. J . Pharmacol. 1995, 283,
199-206.
(19) DeMarinis, R. M.; Wise, M.; Hieble, J . P.; Ruffolo, R. R.
Structure-activity relationships for alpha-1 adrenergic receptor
agonists and antagonists. In The Alpha-1 Adrenergic Receptors;
Ruffolo, R. R., J r., Ed.; Humana Press: Clifton, NJ , 1987; pp
211-267.
(43) Valentin, S. P. Influence of the endothelium and nitric oxide on
the contractile responses evoked by 5-HT1D receptor agonists in
the rabbit isolated saphenous vein. Br. J . Pharmacol. 1996, 119,
35-42.
(20) Schoeffter, P.; Hoyer, D. Interaction of the R-adrenoceptor
agonist oxymetazoline with serotonin 5-HT1A, 5-HT1B, 5-HT1C
,
and 5-HT1D receptors. Eur. J . Pharmacol. 1991, 196, 213-216.
(21) MacKinnon, A. C.; Spedding, M.; Brown, C. M. R2-Adrenocep-
tors: More subtypes but fewer functional differences. Trends
Pharmacol. Sci. 1994, 15, 119-124.
J M970513P