Two conformationally constrained analogs of somatostatin (I) [38916-34-6] were synthesized, cyclo-(ω-aminoheptanoate-Phe-Phe-D-Trp-Lys-Thr-Phe) (II) [70512-60-6] and the bicyclic analog III [70706-79-5], III contained only amino acids 7-10 of I.II, and particularly, III showed high biol. activity.The high activity of II and III indicated that binding of I to receptors was due chiefly to amino acids 7-10.III was relatively resistant to trypsin hydrolysis in vitro but II was cleaved by trypsin at ∼100-fold the rate of hydrolysis of III; the disulfide bond of III appeared to add enzymic stability, either through conformational or steric constraint.Seventy-five minutes after s.c. administration of I, II, and III (50, 50, and 25 μg, resp.) to rats, both II and III inhibited the release of growth hormone (GH) whereas I did not; at 135 min after injection, only III showed inhibition of GH release.Thus, amino acids 7-10 of I, when constrained in the correct conformation, contain receptor binding elements sufficient to express the total activity of I for suppression of the release of insulin, glucagon, and GH.Conformationally constrained structures can therefore be designed to decrease susceptibility to metabolism while retaining biol. activity.
