Synthesis and biological study of novel FELL analogs containing L- or D-tyr instead of L-phe in the N-terminus

• BB9 and BB15 exhibit a more significant analgesic activity compared to this of parent molecules. • The preferable N-terminal substitution is L-Tyr, instead of D-Tyr. • The aromatic OH-group at the N-terminus appears to be essential for interaction with receptors. • All done structural modifications did not lead to improvement of anti-inflammatory properties. • All newly designed FELL analogues save their hydrolytic stability at three different pH. The high prevalence of pain affecting millions of people worldwide made it a major health problem. At the same time often, inflammation is closely associated to the pain. Thus, creation of molecules with a double effect is a good alternative to the currently existing in the medicinal practice non-steroidal medications. Herein, some modifications in the N- and C-terminus of the tetrapeptide FELL with proven anti-inflammatory properties are performed and the newly synthesized compounds are tested for both analgesic and anti-inflammatory potential. The analgesic and anti-inflammatory activity of the newly synthesized molecules was investigated using Paw-pressure and Carrageenan-Induced Paw Edema tests, respectively, on experimental animals. The results showed a certain “discrepancy” between the analgesic and the anti-inflammatory effects of the newly synthesized substances. Newly synthesized BB9 and BB15 , L-Tyr containing C-terminal amide and free acid, respectively, exhibit a more significant analgesic activity compared to those of parent molecules BB1 and BB11 , containing L-Phe in the N-terminus. Moreover, taking into account the obtained results for the compounds BB10 and BB16 , the preferable substitution is L-Tyr, instead of D-Tyr. It could be concluded that the aromatic OH-function is probably important for the connection with the opioid and cannabinoid receptors. However, the designed structural modifications did not lead to improvement in anti-inflammatory effect compared to those of parent molecules. Moreover, in a context of the positive finding is that all modifications done save the hydrolytic stability of the molecules.