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All 5 posts Subject: N-(4-Bromobenzyl)-5-methoxytryptamine Bioassay Please login to post Down

scarmani
(Hive Bee)
03-17-04 08:20
No 495672
User Picture       N-(4-Bromobenzyl)-5-methoxytryptamine Bioassay
(Rated as: good read)

N-(4-Bromobenzyl)-5-methoxytryptamine oxalate was dissolved in 75% ethanol (solubility at room temperature was approximately 2mg/mL). A series of graded doses of solution were administered sublingually in the form of this solution; after a few minutes, the solution was swallowed. No significant unambiguous physiological or psychological effects were observed at any dose. Doses began at 200 µg and the highest dose tested was 7 mg.

The compound is mentioned in this paper by Glennon et al: J.Med.Chem. 37(13); 1929-1935 (1994) (http://www.streamload.com/scarmani/5HT/Influence_of_Amine_Substituents_on_5-HT2A_versus_5-HT2C_Binding_of_Phenylalkyl-_and_Indolylalkylamines.pdf)

In the paper it is measured to have a K_i of 0.1 nM at DOI-labeled human 5-HT2A receptors, as compared to a corresponding K_i of 1.0 nM for alpha-desmethyl-DOB (2CB). Also, based on the large ratio of binding affinity at DOI vs ketanserin labeled 5-HT2A receptors, it was speculatively identified as an agonist.

This compound appeared to be a good candidate for bioassay given the high binding affinity and the relative ease of synthesis (see Post 288584 (slappy: "Receptor profiles", Methods Discourse), also synthesis from paper exerpted below).

Possible reasons for inactivity at the low doses tested: it is not a 5-HT2A agonist; it requires higher doses for oral activity; or perhaps it is not active orally at all due to pharmacokinetic factors (e.g., it is rapidly metabolized because it is only a monosubstituted amine; it is not well absorbed, etc.)

--------------------------

_{The synthesis does not seem very difficult starting from 5-methoxytryptamine: (from the paper)

3-[2-(N-(4-Bromobenzyl)amino)ethyl)]-5-methoxyindole Oxalate

Step 1   (Acylation)
A solution of 4-bromobenzoyl chloride (0.57 g, 2.6 mmol) in dry THF (5 mL) was added in a dropwise manner to a stirred solution of 5-methoxytryptamine (0.5 g, 2.6 mmol) and Et3N (0.52 g, 5.2 mmol) in THF (15 mL) at 0 "C. The reaction mixture was allowed to stir at room temperature overnight; the solid material was removed by fiitration and the filtrate was evaporated to dryness under reduced pressure. A CHCl3 solution of the oily residue was washed successively with 5% HCl (15 mL) and 5% Na2CO3 (100 mL) solutions and dH2O (50 mL). The CHCl3 portion was dried (MgSO4) and the solvent was removed under reduced pressure to afford 0.73 g (74 %) of the amide intermediate as a white solid after recrystallization from Et2O mp 113-115 "C.

Step 2   (Reduction)
AlH3 was prepared by the careful addition of AlCl3 (0.23 g, 1.7 mmol) to a suspension of LiAlH4 (0.22 g, 5.8 mmol) in anhydrous Et2O (15 mL) at 0 "C under a N2 atmosphere. The suspension was stirred for 30 min at room temperature, then a solution of the above amide (0.37 g, 1 mmol) in Et2O (10 mL) was added in a dropwise manner. The reaction mixture was allowed to stir for 5 h at room temperature. Excess AlH3 was decomposed by the addition of crushed ice (1 g) and 20% NaOH solution (2 mL) at 0 "C. The mixture was fiitered and the organic portion of the filtrate was washed with H2O (3 x 15 mL) and dried (MgSO4). The Et2O solution of amine was treated with an Et2O solution of oxalic acid to afford the crude salt; recrystallization from absolute EtOH / anhydrous Et2O gave 0.29 g (67%) of 33 as white crystals: mp 208-210 "C. Anal. (C18H19BrN2O4.C2H2O4)}

stop, drop & roll

Nicodem
(Hive Bee)
03-17-04 09:45
No 495680
User Picture       Possible reasons for inactivity at the low...

Possible reasons for inactivity at the low doses tested: it is not a 5-HT2A agonist; it requires higher doses for oral activity; or perhaps it is not active orally at all due to pharmacokinetic factors (e.g., it is rapidly metabolized because it is only a monosubstituted amine; it is not well absorbed, etc.)

I bet for the first option: "it is not a 5-HT2A agonist"
With such a big group at the amine it is much nearer to the known antagonists than agonists. It might be a partial agonist of very low eficacy so it might require much higher doses especialy if it is not metabolicaly stable enough.

“The real drug-problem is that we need more and better drugs.” – J. Ott

Lilienthal
(Moderator)
03-17-04 10:03
No 495682
User Picture       I'm pretty sure that it is a data bug (if...

I'm pretty sure that it is a data bug (if nothing worse). If you look at the provided data in that article there is an unprecedented extremely sharp structure-affinity peak for the 4-bromo-benzyl. Nobody experienced does take this seriously. My guess would be that it is a medium-affinity antagonist / partial agonist.

scarmani
(Hive Bee)
09-14-04 00:53
No 531204
User Picture       Interesting

There may be something to this structural area after all... Post 530997 (Lego: "5-HT2a agonists with N-2-methoxybenzyl structure", Serious Chemistry) which looks extremely impressive. The question of these new series might be of agonist efficacy (as Lilienthal suggests), and also bioavailability.

boot from the shadow of a broken mirror

Fastandbulbous
(Hive Bee)
09-14-04 07:07
No 531245
User Picture       Removal of N-benzy groups

If I had to make a bet, I would go for it being metabolized to something inactive before much of it gets a chance to interact with the receptor. Other drugs with an N-benzyl group seem to get it cleaved pretty quickly (eg phamacokinetics of benzphetamine).

Damn shame!

That is right, the Mascara Snake: Fast and bulbous

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	All 5 posts		Subject: N-(4-Bromobenzyl)-5-methoxytryptamine Bioassay		Please login to post		Down


		scarmani (Hive Bee) 03-17-04 08:20 No 495672				N-(4-Bromobenzyl)-5-methoxytryptamine Bioassay (Rated as: good read)
						N-(4-Bromobenzyl)-5-methoxytryptamine oxalate was dissolved in 75% ethanol (solubility at room temperature was approximately 2mg/mL). A series of graded doses of solution were administered sublingually in the form of this solution; after a few minutes, the solution was swallowed. No significant unambiguous physiological or psychological effects were observed at any dose. Doses began at 200 µg and the highest dose tested was 7 mg. The compound is mentioned in this paper by Glennon et al: J.Med.Chem. 37(13); 1929-1935 (1994) (http://www.streamload.com/scarmani/5HT/Influence_of_Amine_Substituents_on_5-HT2A_versus_5-HT2C_Binding_of_Phenylalkyl-_and_Indolylalkylamines.pdf) In the paper it is measured to have a K_i of 0.1 nM at DOI-labeled human 5-HT2A receptors, as compared to a corresponding K_i of 1.0 nM for alpha-desmethyl-DOB (2CB). Also, based on the large ratio of binding affinity at DOI vs ketanserin labeled 5-HT2A receptors, it was speculatively identified as an agonist. This compound appeared to be a good candidate for bioassay given the high binding affinity and the relative ease of synthesis (see Post 288584 (slappy: "Receptor profiles", Methods Discourse), also synthesis from paper exerpted below). Possible reasons for inactivity at the low doses tested: it is not a 5-HT2A agonist; it requires higher doses for oral activity; or perhaps it is not active orally at all due to pharmacokinetic factors (e.g., it is rapidly metabolized because it is only a monosubstituted amine; it is not well absorbed, etc.) -------------------------- _{The synthesis does not seem very difficult starting from 5-methoxytryptamine: (from the paper) 3-[2-(N-(4-Bromobenzyl)amino)ethyl)]-5-methoxyindole Oxalate Step 1 (Acylation) A solution of 4-bromobenzoyl chloride (0.57 g, 2.6 mmol) in dry THF (5 mL) was added in a dropwise manner to a stirred solution of 5-methoxytryptamine (0.5 g, 2.6 mmol) and Et3N (0.52 g, 5.2 mmol) in THF (15 mL) at 0 "C. The reaction mixture was allowed to stir at room temperature overnight; the solid material was removed by fiitration and the filtrate was evaporated to dryness under reduced pressure. A CHCl3 solution of the oily residue was washed successively with 5% HCl (15 mL) and 5% Na2CO3 (100 mL) solutions and dH2O (50 mL). The CHCl3 portion was dried (MgSO4) and the solvent was removed under reduced pressure to afford 0.73 g (74 %) of the amide intermediate as a white solid after recrystallization from Et2O mp 113-115 "C. Step 2 (Reduction) AlH3 was prepared by the careful addition of AlCl3 (0.23 g, 1.7 mmol) to a suspension of LiAlH4 (0.22 g, 5.8 mmol) in anhydrous Et2O (15 mL) at 0 "C under a N2 atmosphere. The suspension was stirred for 30 min at room temperature, then a solution of the above amide (0.37 g, 1 mmol) in Et2O (10 mL) was added in a dropwise manner. The reaction mixture was allowed to stir for 5 h at room temperature. Excess AlH3 was decomposed by the addition of crushed ice (1 g) and 20% NaOH solution (2 mL) at 0 "C. The mixture was fiitered and the organic portion of the filtrate was washed with H2O (3 x 15 mL) and dried (MgSO4). The Et2O solution of amine was treated with an Et2O solution of oxalic acid to afford the crude salt; recrystallization from absolute EtOH / anhydrous Et2O gave 0.29 g (67%) of 33 as white crystals: mp 208-210 "C. Anal. (C18H19BrN2O4.C2H2O4)} stop, drop & roll



		Nicodem (Hive Bee) 03-17-04 09:45 No 495680				Possible reasons for inactivity at the low...
						Possible reasons for inactivity at the low doses tested: it is not a 5-HT2A agonist; it requires higher doses for oral activity; or perhaps it is not active orally at all due to pharmacokinetic factors (e.g., it is rapidly metabolized because it is only a monosubstituted amine; it is not well absorbed, etc.) I bet for the first option: "it is not a 5-HT2A agonist" With such a big group at the amine it is much nearer to the known antagonists than agonists. It might be a partial agonist of very low eficacy so it might require much higher doses especialy if it is not metabolicaly stable enough. “The real drug-problem is that we need more and better drugs.” – J. Ott



		Lilienthal (Moderator) 03-17-04 10:03 No 495682				I'm pretty sure that it is a data bug (if...
						I'm pretty sure that it is a data bug (if nothing worse). If you look at the provided data in that article there is an unprecedented extremely sharp structure-affinity peak for the 4-bromo-benzyl. Nobody experienced does take this seriously. My guess would be that it is a medium-affinity antagonist / partial agonist.



		scarmani (Hive Bee) 09-14-04 00:53 No 531204				Interesting
						There may be something to this structural area after all... Post 530997 (Lego: "5-HT2a agonists with N-2-methoxybenzyl structure", Serious Chemistry) which looks extremely impressive. The question of these new series might be of agonist efficacy (as Lilienthal suggests), and also bioavailability. boot from the shadow of a broken mirror



		Fastandbulbous (Hive Bee) 09-14-04 07:07 No 531245				Removal of N-benzy groups
						If I had to make a bet, I would go for it being metabolized to something inactive before much of it gets a chance to interact with the receptor. Other drugs with an N-benzyl group seem to get it cleaved pretty quickly (eg phamacokinetics of benzphetamine). Damn shame! That is right, the Mascara Snake: Fast and bulbous

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