Journal of Medicinal Chemistry p. 1529 - 1538 (1993)
Update date:2022-08-04
Topics:
Street, Leslie J.
Baker, Raymond
Castro, Jose L.
Chambers, Mark S.
Guiblin, Alexander R.
et al.
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 agonist 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 requirements 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 <*> 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.
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Doi:10.1021/jo9917846
(2000)Doi:10.1016/S0040-4039(00)60356-8
(1993)Doi:10.1039/c4ra14130j
(2015)Doi:10.1016/j.carres.2011.04.041
(2011)Doi:10.1021/om00031a030
(1993)Doi:10.1039/c39930000654
(1993)