Development of Specific and Non-Specific Somatostatin Analogs

Summary

Biological activity of six somatostatin analogs has been investigated. In these analogs, disulfide bond is replaced by ethylene bond cyclized with α-amino suberic acid. In addition, they contain unique D-configuration in both Trp⁸ and Cys¹⁴ moiety with dicarba substitution.

An analog of the short chain length, C^ω7 -cyclo(Phe⁶ -Phe⁷ -D-Trp⁸ -Lys⁹ -Thr¹⁰ -Phe¹¹ -D-Asu¹⁴) (analog 4) has suppressive effect for GH, but not for other hormones. Analog 6, C^ω9 -cyclo(Asn⁵ -Phe⁶ -Phe⁷ -D-Trp⁸ -Lys⁹ -Thr¹⁰ -Phe¹¹ -Thr¹² -D-Asu¹⁴), has suppressed GH and insulin secretion, but not for gastrin and glucagon. Analog 1, C^ω11 -cyclo(Lys⁴ -Asn⁵ -Phe⁶ -Phe⁷ -D-Trp⁸ -Lys⁹ -Thr¹⁰ -Phe¹¹ -Thr¹² -Ser¹³ -D-Asu¹⁴) and 5, C^ω9 -cyclo(Lys⁴ -Asn⁵ -Phe⁶ -Phe⁷ -D-Trp⁸ -Lys⁹ -Thr¹⁰ -Phe¹¹ -D-Asu¹⁴) have broad suppressive effect for GH, gastrin, insulin and glucagon release after arginine infusion.

The shortest analog, analog 2, C^ω5 -cyclo(Phe⁷ -D-Trp⁸ -Lys⁹ -Thr¹⁰ -D-Asu¹⁴) has weak suppressive effect of GH, insulin and glucagon secretion, and it is suggested that Phe⁶ and Phe¹¹ are necessary for the appearance of suppressive effect of GH. Specific analog, analog 4, may be useful for the future treatment for acromegaly and diabetic retinopathy. Non-specific analogs, 1 and 5 are candidates for the clinical application of wide variety.

Key-Words

Somatostatin - Biological Activity - Specific and Nonspecific Analog - Growth Hormone - Gastrin - IRI - IRG