Using a solution-phase parallel synthesis strategy, a series of non-peptide somatostatin analogues were prepared, and their binding affinities to the five human somatostatin receptor subtypes (sst(1-5)) were determined. Imidazolyl derivatives 2 were found to bind with moderate affinity but with high selectivity to the sst(3) receptor subtype. Further modifications of these structures led to a more potent class of ligands, the tetrahydro-beta-carboline derivatives 4. Among these, compounds 4k (BN81644) and 4n (BN81674) bind selectively and with high affinity to the sst(3) receptor subtype (K(i) = 0.64 and 0.92 nM, respectively). Furthermore, 4k and 4n reverse the inhibition of cyclic AMP accumulation induced by 1 nM somatostatin via sst(3) receptors, with IC(50) = 2.7 and 0.84 nM, respectively. The most potent compound 4n was shown to be a competitive antagonist of human sst(3) receptors by increasing the EC(50) of SRIF-14-mediated inhibition of cAMP accumulation with a K(B) of 2.8 nM (where K(B) is the concentration of antagonist that shifts the agonist dose-response 2-fold). These new derivatives are, to our knowledge, the first potent and highly selective non-peptide human sst(3) antagonists known and, as such, are useful tools for investigating the physiological role of sst(3) receptors.
2‐Amino‐4‐mercapto‐s‐triazine (IV), an analog of cytosine, has been prepared from cyanuric chloride by a three steps synthesis and by cyclisation of guanylthiourea with ethyl formate.
The mass spectra of compounds III, IV and V have been investigated and fragmentation patterns are presented which account for most of the major ions. Preliminary biological tests are reported.
Die durch Kondensation von Bromessigsäureäthylester mit Arylmethylketonen dargestellten Lävulinsäuren (I) (25‐70% Ausbeute) reagieren mit den Aminen (II) bei 120‐l40°C im Autoklaven in Gegenwart von Wasserstoff und Raney‐Ni zu den Pyrrolidonen (III) [10‐75%; cis‐trans‐Gemische (1:1)].
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