Design and Synthesis of Potent Cystine-Free Cyclic Hexapeptide Agonists at the Human Urotensin Receptor

Cyclic hexapeptides, incorporating a dipeptide unit in place of the disulfide bond found in urotensin, were prepared and screened at the human urotensin receptor. The bridging dipeptide unit was found to influence dramatically the affinity for the urotensin receptor. Alanyl-N-methylalanyl and alanylprolyl dipeptide bridges failed to afford active ligands, while the alanyl-alanyl unit yielded a ligand with submicromolar affinity for the urotensin receptor. Further development led to a hexapeptide agonist with nanomolar affinity (2.8 nM)

Design and Synthesis of Potent Cystine-Free Cyclic Hexapeptide Agonists at the Human Urotensin Receptor

Cyclic hexapeptides, incorporating a dipeptide unit in place of the disulfide bond found in urotensin, were prepared and screened at the human urotensin receptor. The bridging dipeptide unit was found to influence dramatically the affinity for the urotensin receptor. Alanyl-N-methylalanyl and alanylprolyl dipeptide bridges failed to afford active ligands, while the alanyl-alanyl unit yielded a ligand with submicromolar affinity for the urotensin receptor. Further development led to a hexapeptide agonist with nanomolar affinity (2.8 nM)

Synthesis of 1-Benzyl-3-(5‘-hydroxymethyl-2‘-furyl)indazole Analogues as Novel Antiplatelet Agents

1-Benzyl-3-(5‘-hydroxymethyl-2‘-furyl)indazole (28, YC-1) was selected as the lead compound for systemic structural modification. After screening for antiplatelet activity, SARs of YC-1 analogues were established. Among these potent active derivatives, compounds 29, 30, 31, 44, and 45 functioned as potent activators of sGC and inhibitors of PDE5 with potency comparable to that of YC-1. In addition, compound 58 was found to be a selective and potent inhibitor of protease-activated receptor type 4 (PAR4)-dependent platelet activation

Replacement of Phe⁶, Phe⁷, and Phe¹¹ of d-Trp⁸-Somatostatin-14 with l-Pyrazinylalanine. Predicted and Observed Effects on Binding Affinities at hSST2 and hSST4. An Unexpected Effect of the Chirality of Trp⁸ on NMR Spectra in Methanol

An alanine scan performed in the 1970s suggested that Phe6 and Phe11 are required for the binding of somatostatin (SRIF-14). Molecular modeling studies and replacement of Phe6 and Phe11 with a cystine bridge affording ligands with the retention of high biological activity, however, led to the alternate conclusion that Phe6 and Phe11 stabilize the bioactive conformation of SRIF-14. Subsequent studies revealed that Phe11 shields Phe6 in a “herringbone” arrangement. More recently, a report from this laboratory demonstrated that Spartan 3-21G(*) MO calculations can be invaluable in explaining SARs in medicinal chemistry. For example, the ability of benzene and indole rings to bind the Trp8 binding pocket for SRIF-14 and the inability of pyrazine to do so was explained through differences in electrostatic potentials. To investigate the role of Phe6 and Phe11 more fully, we report here the synthesis of two analogues of d-Trp8-SRIF in which Phe6 and Phe11 were replaced by the pryazinylalanine congeners, respectively. The NMR spectra in D2O and the Kis fully support the proposition that Phe11 stabilizes the bioactive conformation through π-bonding or aromatic edge-to-face interaction and that pyrazinylalanine6 can be shielded by Phe11. The data also show unexpectedly that Phe6, via the π-bond, interacts with the receptor, consistent with the original interpretation of the alanine scan. Heretofore it had only been known that Lys9 interacts with an aspartate anion of the receptor. These conclusions are supported by recent studies of Lewis et al. on the effects on Kis of Ala6-SRIF-14-amide at the five receptor subtargets. We also found that pyrazinylalanine7-d-Trp8-SRIF-14 does not bind, suggesting a repulsive interaction with the receptor. Taken together, our results not only validate predictions based on Spartan 3-21G(*) MO analysis but also provide valuable information about the nature of the receptor interaction at the molecular level. Finally, the chirality of Trp8 was unexpectedly found to have a striking effect on NMR spectra in methanol, especially at lower temperatures

Catechol: A Minimal Scaffold for Non-Peptide Peptidomimetics of the <i>i</i> + 1 and <i>i </i>+ 2 Positions of the β-Turn of Somatostatin

The design, synthesis, and evaluation of a series of catechol-based non-peptide peptidomimetics of the peptide hormone somatostatin have been achieved. These ligands comprise the simplest known non-peptide mimetics of the i + 1 and i + 2 positions of the somatostatin β-turn. Incorporation of an additional side chain to include the i position of the β-turn induces a selective 9-fold affinity enhancement at the sst2 receptor

Design, Synthesis, and Binding Affinities of Pyrrolinone-Based Somatostatin Mimetics

Tetrapyrrolinone somatostatin (SRIF) mimetics (cf. 1), based on a heterochiral (d,l-mixed) pyrrolinone scaffold, were designed, synthesized, and evaluated for biological activity. The iterative synthetic sequence, incorporating the requisite functionalized coded and noncoded amino acid side chains, comprised a longest linear synthetic sequence of 23 steps. Binding affinities at two somatostatin receptor subtypes (hsst 4 and 5) reveal micromolar activity, demonstrating that the d,l-mixed pyrrolinone scaffold can be employed to generate functional mimetics of peptide β-turns