Ergoline derivatives as highly potent and selective antagonists at the somatostatin sst1 receptor
摘要:
Non-peptidic compounds containing the octahydro-indolo[4,3-fg]quinoline (ergoline) structural element have been optimized into derivatives with high affinity (pK(d) r sst(1) > 9) and selectivity (> 1000-fold for h sst(1) over h sst(2)-h sst(5)) for the somatostatin sst(1) receptor. In functional assays, these ergolines act as antagonists at human recombinant sst(1) receptors. Pharmacokinetic studies in rodents reveal good oral bioavailability and brain penetration for some of these compounds. (C) 2007 Elsevier Ltd. All rights reserved.
Compounds of the formula
wherein R is primary or secondary C₁-C₈ alkyl, C₂-C₄ alkenyl-CH₂, C₃-C₈ cycloalkyl or C₃-C₆ cycloalkyl-substituted C₁-C₅ primary or secondary alkyl, the total number of carbon atoms in R not to exceed 8; R¹ is allyl, H, or C₁-C₄ straight chain alkyl, and R² is C₁-C₃ alkoxy-C₅-C₇ cycloalkyl; a primary or secondary C₁-C₃ alkoxy-C₂-C₆-alkyl or di(C₁-C₃ alkoxy)-C₂-C₆alkyl; C₃-C₇ ketoalkyl; or C₅-C₇ cycloalkyl or keto-substituted C₅-C₇ cycloalkyl; or 4-hydroxycyclohexyl; or a pharmaceutically-acceptable salt thereof, are useful as 5HT₂ receptor antagonists.