Synthesis and biological activity of 3-[2-(dimethylamino)ethyl]-5-[(1,1-dioxo-5-methyl-1,2,5-thiadiazolidin- 2-yl)-methyl]-1H-indole and analogues: agonists for the 5-HT1D receptor.
A novel series of 5-(1,1-dioxo-1,2,5-thiadiazolidin-2-yl)tryptamines was designed, synthesized, and evaluated as 5-HT1D receptor agonists. Compounds such as 8d,f,k were identified which had comparable affinity, potency, and receptor selectivity to that of the antimigraine drug sumatriptan. Both 8d,k were found to be well absorbed in the rat with oral bioavailabilities of 66% and 62%, respectively. Additionally, 8d was found to be selective over other non-serotonergic receptors and exhibited relatively low central nervous system penetration.
Castro
J L
JL
Chemistry Department, Merck Sharp & Dohme Research Laboratories, Harlow, Essex, U.K.
Baker
R
R
Guiblin
A R
AR
Hobbs
S C
SC
Jenkins
M R
MR
Russell
M G
MG
Beer
M S
MS
Stanton
J A
JA
Scholey
K
K
Hargreaves
R J
RJ
D000818:Animals; D004355:Drug Stability; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D011817:Rabbits; D012501:Saphenous Vein / Q000187:drug effects / Q000502:physiology; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D014363:Tryptamines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*
D007211:Indoles; D017366:Serotonin Receptor Agonists; D013830:Thiadiazoles; D014363:Tryptamines