Objectives: To investigate the relationship between the structure of demorphins (DM) and their pharmacological properties, six analogues of Hyp6DM and Pro6DM were synthesised and their biological activities were studied. Methods: The peptides were synthesised by the solid phase method using 9-fluorenylmethoxycarbonyl amino acid trichlorophenyl esters as coupling agents and Merrifield resin as solid support. The opioid agonist activity was studied using co-axially, electrically stimulated contraction of isolated guinea pig ileum (GPI, in vitro). Their analgesic activity was assessed in mice using Eddy's hot plate method and tail-flick method. The antidiarrhoeal activity was determined by the charcoal meal test in mice. Results: In the GPI assay, the synthetic analogues possess agonistic activity that are less pronounced than morphine. Peptides I and II (substitution of ser of position 7 and Gly at position 4 in Hyp6DM series respectively) possessed considerable analgesic activity but are almost inactive in the GPI assay. Peptide III (Pro6, Sar7DM) possess only analgesic activity. In GPI assay, peptide IV was inactive. Peptide V and VI had equipotent analgesic and antidiarrhoeal activity. Conclusion: Peptides with various structures can possess specificities that may prove useful in biological applications. Among them Sar4, Hyp6, Tyr7DM, Hyp6, Pro7DM, Pro6, Sar DM and Phg3, ProDM exhibited a high degree of selectivity in their activities
