Synthesis and Pharmacological Activity of Fluorinated Tryptamine Derivatives

Kalir, A.; Szara, Stephen

doi:10.1021/jm00342a019

Cited by 35 publications

(20 citation statements)

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“…All other reagents were of highest available purity and were purchased from Sigma (Israel). The following compounds were synthesized by Professer Kalir: K-502, 3-(3'-isopropylaminobutyl) indole hydrochloride; K-511, 6-fluoro-a-methyltryptamine hydrochloride (Kalir & Balderman, 1968); K-622, 4-trifluoromethyl-a-methyl-tryptamine bimalmate (Kalir, Pelah & Balderman, 1967); Ka, N-ethyl-a-methyltryptamine hydrochloride (Kalir & Szara, 1966); Kb, N-isopropyl-a-methyltryptamine hydrochloride (Kalir & Szara, 1966); Kc, 3-(3'-ethylaminobutyl) indole hydrochloride (Kalir & Szara, 1966) and Kd, 5-fluoro-a-methyltryptamine hydrochloride (Kalir & Szara, 1963). The compounds K-Y 1243, Nmethyl-N-propartyl-l-phenyl-cyclohexylamine hydrochloride; K-Y 1249, N-propargyl-l-phenylcyclohexylamine hydrochloride; K-Y 1314, Npropargyl-l-phenylcyclohexyl-methylamine hydrochloride were synthesized from a phencyclidine derivative (Kalir & Youdim, unpublished).…”

Section: Methodsmentioning

confidence: 99%

Selective Acetylenic ‘Suicide’ and Reversible Inhibitors of Monoamine Oxidase Types a and B

Kalir

Sabbagh

Youdim

1981

British J Pharmacology

130

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1 A number of aromatic-N-propargyl (acetylenic) compounds and indoleamines were tested for their inhibitory action on monoamine oxidase (MAO) type A and type B using the substrates 5-hydroxytryptamine (5-HT), f3-phenylethylamine (PEA) and dopamine.2 Structure activity studies with aromatic-N-propragyl (acetylenic) derivatives have shown that MAO inhibitory potency is least dependent on the aromatic portion of the compounds. N-methylated propargyl derivatives are the most active and replacement of the methyl group with a higher alkyl or aromatic group results in significant reduction of activity. The triple bond in the N-propargyl portion-is absolutely essential for activity and must be 8-to the nitrogen. It is the acetylenic group that gives these compounds their irreversible MAO inhibitory property. 3 The present study has indicated that since the acetylenic compounds resemble the enzyme substrates the distance between the aromatic ring and the N-propargyl terminal is crucial in designating the type A or type B MAO inhibitory property. For MAO type A inhibition, a distance equivalent to at least three carbon units is required, while for the inhibition of the B type enzyme this distance can be 1 or 2 carbon units. 4 The compounds AGN-1133 and AGN-1135 show most promise in Parkinson's disease or as anti-depressants because of their irreversible selective type B MAO inhibition in vitro and in vivo. 5 A number of indoleamine derivatives were found to be reversible selective type A inhibitors.

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Section: Methodsmentioning

confidence: 99%

Selective Acetylenic ‘Suicide’ and Reversible Inhibitors of Monoamine Oxidase Types a and B

Kalir

Sabbagh

Youdim

1981

British J Pharmacology

130

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“…5 A more recent study showed that it did not possess LSD-or 1-(2,5-dimethoxy-4-iodopheny)-2-aminopropane (DOI)-like activity in a drug discrimination study in rats trained to discriminate these drugs from saline.…”

Section: Ring Substituentsmentioning

confidence: 99%

“…With respect to utility as a radioligand, the α-methyl compound had no advantage over the simpler phenethylamines. That is, for use as a radioligand to label 5 Incorporation of the α-methyl into a cyclopropane ring gives substituted 2-phenylcyclopropylamines with high potency, both in vitro and in vivo. In vivo potency for the cis-and trans-cyclopropane analogs of mescaline was first reported by Cooper and Walters.…”

Section: Effect Of α-Alkylationmentioning

confidence: 99%

Structure–activity relationships of serotonin 5‐HT_2A agonists

Nichols

2012

WIREs Membr Transp Signal

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Of the 14 known types of serotonin receptors one of the most extensively studied is the 5-HT 2A (5-hydroxytryptamine) receptor. In the brain, this receptor plays a key role in regulation of cortical function and cognition, appears to be the principal target for the hallucinogenic/psychedelic drugs such as lysergic acid diethylamide (LSD), and also is a target for the newest atypical antipsychotic agents, which are antagonists or inverse agonists at this site. Among the structure-activity relationships that are known for this receptor type, there are three chemical classes of agonists: tryptamines, ergolines, and phenethylamines. Important structural features are identified for agonist activity and some of these agonists have features in common. In addition to effects at the receptor will be the focus, these drugs are also hallucinogenic (psychedelic) agents, and much of the SAR was developed on the basis of effects in humans, before modern pharmacological techniques were available. A certain amount of our knowledge therefore relies on those human studies.

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“…The procedures utilized for the synthesis of indole-3-carboxaldehydes and their halogenated derivatives were those reported previously by Jiang et al13, Johnson et al15, Kalir and Szara22, Noland and Reich23, James and Snyder24, and Somei et al25. Briefly, Phosphorus (V) oxychloride (4.25 g, 0.028 mol) was added drop wise to DMF (6 mL) cooled in an ice bath.…”

Section: Methodsmentioning

confidence: 99%

Synthesis and structure–affinity relationships of novel small molecule natural product derivatives capable of discriminating between serotonin 5-HT1A, 5-HT2A, 5-HT2C receptor subtypes

Cummings

Canseco

Sheth

et al. 2010

Bioorganic & Medicinal Chemistry

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Efforts to develop ligands that distinguish between clinically relevant 5-HT2A and 5-HT2C serotonin receptor subtypes have been challenging, because their sequences have high homology. Previous studies reported that a novel aplysinopsin belonging to a chemical class of natural products isolated from a marine sponge was selective for the 5-HT2C over the 5-HT2A receptor subtype. Our goal was to explore the 5-HT2A/2C receptor structure-affinity relationships of derivatives based on the aplysinopsin natural product pharmacophore. Twenty aplysinopsin derivatives were synthesized, purified and tested for their affinities for cloned human serotonin 5-HT1A, 5-HT2A and 5-HT2C receptor subtypes. Four compounds in this series had >30-fold selectivity for 5-HT2A or 5-HT2C receptors. The compound (E)-5-((5,6-dichloro-1H-indol-3-yl)methylene)-2-imino-1,3-dimethylimidazolidin-4-one (UNT-TWU-22, 16) had approximately 2100-fold selectivity for the serotonin 5-HT2C receptor subtype: an affinity for 5-HT2C equal to 46 nM and no detectable affinity for the 5-HT1A or 5-HT2A receptor subtypes. The two most important factors controlling 5-HT2A or 5-HT2C receptor subtype selectivity were the combined R1, R3-alkylation of the imidazolidinone ring and the type and number of halogens on the indole ring of the aplysinopsin pharmacophore.

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Synthesis and Pharmacological Activity of Fluorinated Tryptamine Derivatives

Cited by 35 publications

References 0 publications

Selective Acetylenic ‘Suicide’ and Reversible Inhibitors of Monoamine Oxidase Types a and B

Selective Acetylenic ‘Suicide’ and Reversible Inhibitors of Monoamine Oxidase Types a and B

Structure–activity relationships of serotonin 5‐HT_2A agonists

Synthesis and structure–affinity relationships of novel small molecule natural product derivatives capable of discriminating between serotonin 5-HT1A, 5-HT2A, 5-HT2C receptor subtypes

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Synthesis and Pharmacological Activity of Fluorinated Tryptamine Derivatives

Cited by 35 publications

References 0 publications

Selective Acetylenic ‘Suicide’ and Reversible Inhibitors of Monoamine Oxidase Types a and B

Selective Acetylenic ‘Suicide’ and Reversible Inhibitors of Monoamine Oxidase Types a and B

Structure–activity relationships of serotonin 5‐HT2A agonists

Synthesis and structure–affinity relationships of novel small molecule natural product derivatives capable of discriminating between serotonin 5-HT1A, 5-HT2A, 5-HT2C receptor subtypes

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Product

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Structure–activity relationships of serotonin 5‐HT_2A agonists