Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: CAS:3685-25-4 (4-aminocyclohexanecarboxylic acid)
 9 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Synthesis and opioid activity of dynorphin A-(1-13)NH2 analogues containing cis- and trans-4-aminocyclohexanecarboxylic acid. 809 77

A discovery approach based on an intramolecular inhibitory mechanism was applied to a prototype calmodulin (CaM)-regulated protein kinase in order to demonstrate a proof-of-principle for the development of selective inhibitors. The overall approach used functional genomics analysis of myosin light chain kinase (MLCK) to identify short autoinhibitory sequences that lack CaM recognition activity, followed by recursive combinatorial peptide library production and comparative activity screens. Peptide 18 (Arg-Lys-Lys-Tyr-Lys-Tyr-Arg-Arg-Lys-NH2), one of several selective inhibitors discovered, has an IC50 = 50 nM for MLCK, inhibits CaM kinase II only at 4000-fold higher concentrations, and does not inhibit cyclic AMP-dependent protein kinase. Analogues of peptide 18 containing conformationally constrained cis-4-aminocyclohexanecarboxylic acid retained affinity and selectivity. The inhibitors add to the armamentarium available for the deconvolution of complex signal transduction pathways and their relationship to homeostasis and disease, and the approach is potentially applicable to enzymes in which the catalytic and regulatory domains are found within the same open reading frame of a cDNA.
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PMID:Identification of novel classes of protein kinase inhibitors using combinatorial peptide chemistry based on functional genomics knowledge. 1007 88