The Vespiary

Novel Agonists of 5HT_2C Receptors
Synthesis and Biological Evaluation of Substituted 2-(Indol-1-yl)-1-methylethylamines and 2-(Indeno[1,2-b]pyrrol-1-yl)-1-methylethylamines
Improved Therapeutics for Obsessive Compulsive Disorder
Michael Bös, Francois Jenck, James R. Martin, Jean-Luc Moreau, Andrew J. Sleight, Jürgen Wichmann, and Ulrich Widmer
J. Med. Chem. 1997, 40, 2762-2769
DOI:

10.1021/jm970030l (http://dx.doi.org/10.1021/jm970030l)

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Abstract
The syntheses of a series of substituted 2-(indol-1-yl)-1-methylethylamines and 2-(indeno[1,2-b]pyrrol-1-yl)-1-methylethylamines are reported. The binding affinities of the compounds at 5HT_2C and 5HT_2A receptors (79% homology in the transmembrane domain) were determined. The ligands displayed selectivity for 5HT_2C receptors relative to 5HT_2A receptors. Compounds were functionally characterized both in vitro and in vivo as 5HT_2C receptor agonists. 5f, 5l, 5n, 5o, 5q, 14c, 14f, 14k, and 14m exhibited anticompulsive activity in an animal model of obsessive compulsive disorder.

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Scheme 1 (a) Propylene oxide, NaH, THF; (b) MsCl, NEt₃, CH₂Cl₂; (c) NaN₃, DMF; (d) PtO₂, H₂, EtOH.

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Scheme 3 (a) 3-Buten-2-ol, p-TsA, 2,2-dimethoxypropane; (b) ozone, CH₂Cl₂-MeOH; (c) TFA, CH₂Cl₂; (d) 1-amino-2-propanol, p-TsA, toluene; (e) MsCl, NEt₃, CH₂Cl₂; (f) NaN₃, DMF; (g) PtO₂, H₂, EtOH.

This is reference #6, which I find interesting:

Synthesis and Pharmacological Activity of Fluorinated Tryptamine Derivatives
Asher Kalir, Stephen Szara, J. Med. Chem. 6, 716-719 (1963)

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Abstract
The synthesis of several fluorinated tryptamine derivatives in which the fluorine atom occupies the 5- or  6-position is reported. The 5-fluoro and unsubstituted tryptamines are more active than the 6-substituted derivatives in inducing spontaneous locomotion when administered to reserpinized white mice. Both 6-fluoro-N,N-diethyltryptamine  and N,N-diethyltryptamine exerted peripheral activity when tested in humans, hut only the fluorine-free compound seemed to bear hallucinogenic properties. These results may be explained by change in the metabolic pathway of the tryptamines with substituted 6-position in the indole nucleus.

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The effect of 6-fluorodiethyltryptamine was compared with diethyltryptamine (DET) in six patients and one normal volunteer. Both drugs were given intramuscularly in 1 mg./kg. doses. DET produced sympathomimetic autonomic symptoms, perceptual disturbances, hallucinations, mood changes, and difficulties in thinking and speaking. The 6-fluoro analog in the same persons produced the autonomic symptoms and mood changes without the perceptual and thinking disturbances so characteristic of hallucinogenic drugs.

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Shulgin comments in

Tihkal #3: DET (http://www.erowid.org/library/books_online/tihkal/tihkal03.shtml)

(http://www.erowid.org/library/books_online/tihkal/tihkal03.shtml):

As a challenge to the hypothesis that hydroxylation at the 6-position of the N,N-dialkyltryptamines might play some role in the expression of the activity, this position was metabolically blocked by the insertion of a fluorine atom there, giving 6-F-DET. This compound, with DET as the control, was studied in some twelve hospitalized alcoholics at doses of about 60, 80 and 100 milligrams intramuscularly. It "does produce autonomic effects, pupillary changes, blood pressure changes; but it does not produce the drifting away into a dream world and other phenomena characteristic for the hallucinogenic activity." The experimenters considered its possible experimental role as an "active placebo" but nothing more was done with it.

An active placebo mimics the side effects of the experimental drug, as using a standard "sugar pill" would be pointless in the case of psychedelic drugs - there is usually no question about you having taken the drug or not.

Indoline derivatives as 5-HT_2C receptor agonists
J. M. Bentley, D. R. Adams, D. Bebbington, K. R. Benwell, M. J. Bickerdike, J. E. P. Davidson, C. E. Dawson, C. T. Dourish, M. A. J. Duncton, S. Gaur, A. R. George, P. R. Giles, R. J. Hamlyn, G. A. Kennett, A. R. Knight, C. S. Malcolm, H. L. Mansell, A. Misra, N. J. T. Monck, R. M. Pratt, K. Quirk, J. R. A. Roffey, S. P. Vickers and I. A. Cliffe
Bioorg. Med. Chem., 2004, 14, 2367-2370
DOI:

10.1016/j.bmcl.2003.05.001 (http://dx.doi.org/10.1016/j.bmcl.2003.05.001)

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Abstract
A series of 1-(1-indolinyl)-2-propylamines was synthesised and evaluated as 5-HT_2C receptor agonists for the treatment of obesity. The general methods of synthesis of the precursor indoles are described. The functional efficacy and radioligand binding data for all of the compounds at 5-HT2 receptor subtypes are reported. A number of compounds were found to reduce food intake in rats after oral administration.

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Cycloalkyl[b][1,4]benzodiazepinoindoles are agonists at the human 5-HT_2C receptor
Annmarie L. Sabb, Robert L. Vogel, Gregory S. Welmaker, Joan E. Sabalski, Joseph Coupet, John Dunlop, Sharon Rosenzweig-Lipsonb and Boyd Harrison
Bioorg. Med. Chem., 2004,
DOI:

10.1016/j.bmcl.2004.02.100 (http://dx.doi.org/10.1016/j.bmcl.2004.02.100)

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Abstract
Evaluation of selected compounds from our Corporate Compound Library in a human 5-HT_2C receptor binding assay led to the discovery of WAY-629, a cyclohexyl[b][1,4]benzodiazepinoindole (K_i 56 nM, E_max 90%), which is selective for the 5-HT_2C receptor versus other serotonin receptor subtypes, and dopamine, histamine, adrenergic, and muscarinic receptors. In addition, WAY-629 was active in vivo in a rat model of feeding behavior. An SAR study based on WAY-629 led to compound 11 (K_i 13 nM, E_max102%).

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2,3,4,5-Tetrahydro- and 2,3,4,5,11,11a-Hexahydro-1H-[1,4]diazepino[1,7-a]indoles: New Templates for 5-HT_2C Agonists
Michael D. Ennis, Robert L. Hoffman, Nabil B. Ghazal, Rebecca M. Olson, Christopher S. Knauer, Chris L. Chio, Deborah K. Hyslop, Jeffery E. Campbell, Lawrence W. Fitzgerald, Nanette F. Nichols, Kjell A. Svensson, Robert B. McCall, Christopher L. Haber, Michelle L. Kageyc and Dac M. Dinh
Bioorg. Med. Chem. Lett., 2003, 13(14), 2369-2372
DOI:

10.1016/S0960-894X(03)00403-7 (http://dx.doi.org/10.1016/S0960%2D894X%2803%2900403%2D7)

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Abstract: The design and synthesis of the novel 2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole 5 is described. This azepinoindole has excellent affinity for 5-HT_2C (Ki 4.8 nM) and modest selectivity over 5-HT_2A (~4-fold). Several N- and C₁₁-substituted analogues of 5 were prepared, as were a number of biaryl indoline derivatives. The anxiolytic potential for the azepinoindole template 5 is demonstrated by activity in a mouse shock–aggression assay.
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