Synthesis and serotonergic activity of 5-(oxadiazolyl)tryptamines: potent agonists for 5-HT1D receptors.
The synthesis and 5-HT1D receptor activity of a novel series of 5-(oxadiazolyl)tryptamines is described. Modifications of the oxadiazole 3-substituent, length of the linking chain (n), and the amine substituents are explored and reveal a large binding pocket in the 5-HT1D receptor domain. Oxadiazole substituents such as benzyl are accommodated without loss of agonist potency or efficacy. The incorporation of polar functionality on a phenyl or benzyl spacer group results in a 10-fold increase in affinity and functional potency. Optimal 5-HT1D activity is observed when the heterocycle is conjugated with the indole and the benzyl sulfonamides 20t and 20u represent some of the most potent 5-HT1D agonists known. Replacement of O for S in the heterocycle leads to a further increase in potency. Deletion of oxadiazole N-2 does not reduce activity, suggesting the requirement for only one H-bond acceptor in this location. The selectivity of these compounds for 5-HT1D receptors over other serotonergic receptors is discussed. Sulfonamide 20t shows > or = 1000-fold selectivity for 5-HT1D over 5-HT2, 5-HT1C, and 5-HT3 receptors and 10-fold selectivity with respect to 5-HT1A receptors. The functional activity of this series of compounds is studied and demonstrates high 5-HT1D receptor potency and efficacy comparable to that of 5-HT.
Street
L J
LJ
Chemistry Department, Merck Sharp and Dohme Research Laboratories, Harlow, Essex, U.K.
Baker
R
R
Castro
J L
JL
Chambers
M S
MS
Guiblin
A R
AR
Hobbs
S C
SC
Matassa
V G
VG
Reeve
A J
AJ
Beer
M S
MS
Middlemiss
D N
DN
D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D066298:In Vitro Techniques; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011817:Rabbits; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013552:Swine; D014363:Tryptamines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects
D010069:Oxadiazoles; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D014363:Tryptamines