Design, Synthesis, and Biological Activities of Potent and Selective Somatostatin Analogues Incorporating Novel Peptoid Residues

Abstract

We report the synthesis, bioactivity, and structure-activity relationship studies of compounds related to the Merck cyclic hexapeptide c[Pro6-Phe7-d-Trp8-Lys9-Thr10-Phe11], L-363,301 (the numbering in the sequence refers to the position of the residues in native somatostatin). The Pro residue in this compound is replaced with arylalkyl peptoid residues. We present a novel approach utilizing beta-methyl chiral substitutions to constrain the peptoid side-chain conformation. Our studies led to molecules which show potent binding and increased selectivity to the hsst2 receptor (weaker binding to the hsst3 and hsst5 receptors compared to L-363, 301). In vivo, these peptoid analogues selectively inhibit the release of growth hormone but have no effect on the inhibition of insulin. The biological assays which include binding to five recombinant human somatostatin receptors carried out in two independent laboratories and in vivo inhibition of growth hormone and insulin provide insight into the relationship between structure and biological activity of somatostatin analogues. Our results have important implications for the study of other peptide hormones and neurotransmitters.

International Union of Pharmacology. LXVIII. Mammalian Bombesin Receptors: Nomenclature, Distribution, Pharmacology, Signaling, and Functions in Normal and Disease States

“…PD 168368 is a new class of antagonists described as a peptoid, because this group of antagonists are nonpeptide ligands, which were designed using the chemical structure of the mammalian neuropeptide of interest as a stating point Horwell, 1995). This approach has yielded antagonists for cholecystokinin, somatostatin, tachykinins, and bombesin receptors (Boden et al, 1993;Boyle et al, 1994;Horwell et al, 1994;Horwell, 1995;Eden et al, 1996;Tran et al, 1998;Tokita et al, 2001a). However, little is known about the molecular basis of their affinity and whether they resemble peptide or other nonpeptide ligands in the basis of their selectivity and affinity (Tokita et al, 2001a).…”

Tyrosine 220 in the 5th Transmembrane Domain of the Neuromedin B Receptor Is Critical for the High Selectivity of the Peptoid Antagonist PD168368

“…These peptoids may act as either agonists or antagonists at neuropeptide receptors. To date, several classes of peptoid antagonists for receptors of gastrointestinal (GI) 1 hormones/neurotransmitters have been described including for cholecystokinin (3)(4)(5), somatostatin (6), tachykinins (7)(8)(9), or bombesin (10) receptors. They have been proven useful in helping to examine the role of these receptors in mediating various physiological and pathophysiological processes and they may be useful as therapeutic agents in such conditions as panic attacks (1,2,5).…”

Strategies for drug delivery to the central nervous system by systemic route

“…There were also attempts to mimic somatostatin, a growth hormone, and azapeptide, a T-cell activator (Tran et al, 1998;Hart & Beeson, 2001) using this technology. Similarly, modifications can be carried out to synthesize peptide resembling a naturally occurring biological substance with suitable modification to obtain desirable properties so that the molecules are able to cross BBB.…”