Análisis e interpretación de Resultados (Encuesta a Docentes

The KWF mimic compounds display high inhibition of somatostatin at SSTR2 which was expected as they were based on existing SSTR2 ligands. Likewise the

91 KWFQ mimics based on the existing SSTR2 ligands with the addition of the lactam also showed high binding, this shows the addition of the lactam does not have a negative effect on their SSTR2 binding ability. The IC50's show the KWF mimics are more potent however with compound 2.51 having an approximate 100-fold increase over compound 2.94. The IC50's for compounds 2.45, 2.51 and compounds very close in structure to 2.01 have been reported as 85, 0.26 and between 2.6-2.9 nM.140 These are close to the values reported herein.

Both the KWF and KWFQ mimics show high inhibition of leukocyte migration at a concentration of 1 µM. At a concentration of 1 nM all of the compounds retain this high activity apart from compound 2.94. This correlates with the IC50 values to a certain extent as compound 2.94 has the highest value. This indicates that in these compounds the ability to displace somatostatin from SSTR2 is linked with the compounds BSCI ability.

It is unexpected however that the KWF compounds act as BSCIs despite lacking the WxQ motif thought essential for BSCI activity. Previous studies have shown while cyclic peptides containing KWIQ act as BSCIs those containing KWI have no BSCI activity and in fact act as inhibitors. BIM58079D, BIM58092D and BIM58078D (compounds 2.95-2.97) all contain WIQ and have leukocyte migration inhibition potencies of 12, 20 and 80 nM respectively (Figure 64). BIM23454 (compound 2.98) is a cyclic peptide containing a KWx motif of lysine, (D)-tryptophan and pyridinyl alanine (Pal) (Cpa stands for p-chlorophenylalanine and NaI stands for 3-(2- napthyl)alanine). Compound 2.98 has an IC50 value of 2.6 nM139 for the displacement of somatostatin from SSTR2, lacking the WxQ motif it is a potent antagonist against the action of compounds with BSCI activity. This evidence

92 supports the need the WxQ motif for a compound to have BSCI activity. However the fact that the peptide-like compounds we synthesised did not contain the glutamine residue but still retained BSCI activity suggests that conclusions based on the cyclic BSCIs do not necessarily hold true for the acyclic BSCIs.

Figure 64 Compounds 2.95-2.98

Hoyer and colleges have studied the ability of SSTR2 ligands to inhibit forskolin- stimulated adenylate cyclase and thus the production of cyclic adenosine monophosphate (cAMP).201 The results for compound 2.51 and compounds 1.39 and 2.100 (similar in structure to compound 2.01) gave inhibition values of 117.9, 117.5 and 119.1 % respectively. These values correlate with the leukocyte migration inhibition data and could indicate cAMP inhibition correlates with leukocyte migration inhibition. To gain more information on this theory the data is required on the inhibition of cAMP for compound 2.45 as well as the KWFQ mimics 2.05 and 2.94. As somatostatin is a growth hormone regulator the KWQ and KWFQ mimics could also be tested as to their ability to regulate growth hormone.

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Figure 65 Compounds 1.39, 2.01 and 2.100 synthesised by Hay and colleges140

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