4-aryl-substituted 2,5-dimethoxyphenethylamines: synthesis and serotonin 5-HT(2A) receptor affinities.
A series of novel ligands for the serotonin 5-HT(2A/C) receptor subtype bearing the 2-phenylethylamine pharmacophore was synthesized and assayed for its 5-HT(2A) receptor binding affinity. As the 4'-aryl-substituted 2-(2,5-dimethoxyphenyl)ethylamines were previously unknown, an initial series of twelve compounds was chosen to obtain initial insight into their structure-activity relationships. The 4'-aryl moiety was introduced in moderate-to-high yield by a Pd-catalyzed Suzuki reaction of twelve arylboronic acids with N-Boc-protected 2-(2,5-dimethoxy-4-iodophenyl)ethylamine (8). N-Boc Deprotection then afforded the novel 2-phenylethylamines 5a-5l. Additionally, biphenyl compound 6 lacking the 5'-MeO substituent was prepared, starting from 2-methoxy-4-hydroxybenzaldehyde. Except for 5l, all of the compounds proved to be antagonists with generally low affinity at the rat 5-HT(2A) receptor. Substituents are generally not well tolerated on the 4'-aryl moiety, except in the 4''-position. Indeed, the relatively high affinity of the 4''-butyl-, 4''-phenyl-, and 4'-naphthyl-substituted compounds 5i, 5k, and 5e, respectively (K(i)=32, 33, and 41nM, resp.), attests a rather remarkable tolerance for bulk in this location.
Trachsel
Daniel
D
Chemistry Department of the Bern University of Applied Sciences, Burgdorf. daniel_trachsel@gmx.ch
Nichols
David E
DE
Kidd
Stephanie
S
Hadorn
Marcel
M
Baumberger
Franz
F
D000818:Animals; D002460:Cell Line; D051379:Mice; D041681:NIH 3T3 Cells; D010627:Phenethylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
D010627:Phenethylamines; D044402:Receptor, Serotonin, 5-HT2A