The Synthesis of γ-3,4,5,6-Tetrachlorocyclohexene (γ-BTC) by Means of a Diels-Alder Reaction

The search for synthetic analogues of somatostatin which exhibit selective affinities for the five receptor subtypes is of considerable basic and therapeutic interest and has generated a large number of potent agonist analogues with a wide spectrum of binding profiles. In the past, conformational restriction of side chain groups and the peptide backbone has yielded the most interesting results. Under the latter category and as part of the present study, we were interested in the potential effects of N-methylation of peptide bond NH groups on binding affinity since this approach had not been systematically examined with these peptides. This was aided by new chemistries for introducing an N-Me group during regular solid-phase peptide synthesis using Boc protection. A number of interesting effects were noted on relative binding affinities of the two series of agonist sequences chosen, DPhe(5)(or Tyr(5))-c[Cys(6)-Phe(7)-DTrp(8)-Lys(9)-Thr(10)-Cys(11)]Thr(12)-NH(2) (SRIF numbering), at the five known human somatostatin receptors transfected into and stably expressed by CHO cells. N-Methylation of residues 7 (Phe), 10 (Thr), 11 (Cys), and 12 (Thr) largely destroyed affinities for all five receptors. N-Methylation of DTrp in the DPhe series gave an analogue with extraordinarily high affinity for the type 5 receptor for which it was also quite selective. N-Methylation of Lys in both series resulted in retention of type 2 affinity despite this residue constituting the "active center" of somatostatin peptides. N-Methylation of either the N-terminal Tyr residue or of Cys(6) in the Tyr series resulted in analogues with extraordinarily high affinity for the type 3 receptor, also with a degree of specificity. N-Methylation of the peptide bond constrains the conformational space of the amino acid and eliminates the possibility of donor hydrogen bond formation from the amide linkage. The beta-bend conformation of the agonists around DTrp-Lys is stabilized by a transannular intramolecular hydrogen bond(s) between Phe(7) and Thr(10) so methylation of these residues eliminates this source of stabilization. It is expected that several of these analogues will provide additional tools for determining some of the physiological roles played by type 3 and 5 somatostatin receptors which are still far from being fully elucidated.

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The Synthesis of γ-3,4,5,6-Tetrachlorocyclohexene (γ-BTC) by Means of a Diels-Alder Reaction

Cited by 2 publications

References 10 publications

ChemInform Abstract: THE SYNTHESIS OF GAMMA‐3,4,5,6‐TETRACHLOROCYCLOHEXENE (GAMMA‐BTC) BY MEANS OF A DIELS‐ALDER′ REACTION

ChemInform Abstract: THE SYNTHESIS OF GAMMA‐3,4,5,6‐TETRACHLOROCYCLOHEXENE (GAMMA‐BTC) BY MEANS OF A DIELS‐ALDER′ REACTION

N-Methyl Scan of Somatostatin Octapeptide Agonists Produces Interesting Effects on Receptor Subtype Specificity

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