Ergoline derivatives as highly potent and selective antagonists at the somatostatin sst 1 receptor.
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.
Troxler
Thomas
T
Neuroscience Chemistry, Novartis Institutes for BioMedical Research, WSJ-088.3.06, CH-4002 Basel, Switzerland. thomas.troxler@novartis.com
Enz
Albert
A
Hoyer
Daniel
D
Langenegger
Daniel
D
Neumann
Peter
P
Pfäffli
Paul
P
Schoeffter
Philippe
P
Hurth
Konstanze
K
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004873:Ergolines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D015394:Molecular Structure; D051381:Rats; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors*; D013004:Somatostatin / Q000502:physiology
D004873:Ergolines; D017481:Receptors, Somatostatin; D013004:Somatostatin