Synthesis and opioid activity of dynorphin A-(1-13)NH2 analogues containing cis- and trans-4-aminocyclohexanecarboxylic acid.
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 of Dyn 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 kappa opioid receptors (Ki's = 9.1 and 13.4 nM for [cis-ACCA2-3]- and [trans-ACCA2-3]Dyn A-(1-13)NH2, respectively) and modest kappa-receptor selectivity (Ki ratio (kappa/mu/delta) = 1/13/210 and 1/21/103, respectively). [cis-ACCA2-3]- and [trans-ACCA2-3]Dyn A-(1-13)-NH2 are the first reported Dyn A analogues constrained in the "message" sequence that are selective for kappa receptors. The cis-ACCA analogue showed very weak opioid activity (IC50 = 4.0 microM) in the guinea pig ileum.
Snyder
K R
KR
Oregon State University, College of Pharmacy, Corvallis 97331.
Murray
T F
TF
DeLander
G E
GE
Aldrich
J V
JV
D000596:Amino Acids / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D003509:Cyclohexanecarboxylic Acids / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D004399:Dynorphins / Q000494:pharmacology*; D006168:Guinea Pigs; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D009294:Narcotics / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017473:Receptors, Opioid, kappa / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000596:Amino Acids; D003509:Cyclohexanecarboxylic Acids; D009294:Narcotics; D010446:Peptide Fragments; D017473:Receptors, Opioid, kappa; C026843:dynorphin (1-13); D004399:Dynorphins