Synthesis and Opioid Activity of Dynorphin A-(1-13)NH2 Analogues Containing cis- and trans-4-Aminocyclohexanecarboxylic acid

Article abstract of DOI:10.1021/jm00060a018

It has been proposed that the "message" sequence of dynorphin A (Dyn A) exists in an extended conformation in aqueous solution (Schiller, P.W.Int.J.Pept.Protein Res. 1983, 21 307-312).Molecular modeling suggested that trans-4-aminocyclohexanecarboxylic acid (trans-ACCA) might function as a conformationally constrained replacement for Gly²-Gly³ of Dyn A in such an extended conformation.ACCA was synthesized by catalytic hydrogenation of p-aminobenzoic acid, and the cis and trans isomers were separated by fractional recrystallization.Analogues ofDyn A-(1-13)-NH2 containing cis- and trans-ACCA were prepared by solid-phase peptide synthesis using the Fmoc chemical protocol.Results from radioligand binding assays indicated that the peptides have modest affinity for κ opioid receptors (K_i's = 9.1 and 13.4 nM for 2-3>- and 2-3>Dyn A-(1-13)NH2, respectively) and modest κ-receptor selectivity (K_i ratio (κ/μ/δ) = 1/13/210 and 1/21/103, respectively) 2-3>- and 2-3>Dyn A-(1-13)-NH2 are the first reported Dyn A analogues constrained in the "message" sequence that are selective for κ receptors.The cis-ACCA analogue showed very weak opioid activity (IC50 = 4.0 μM) in the guinea pig ileum.