Design and synthesis of highly potent and selective cyclic dynorphin A analogs. 2. New analogs

Article abstract of DOI:10.1021/jm00058a012

We have designed and synthesized several cyclic disulfide-containing peptide analogs of dynorphin A (Dyn A) which are conformationally constrained in the putative 'address' segment of the opioid ligand. Several of these Dyn A analogs exhibit unexpected apparent selectivities for the κ and μ opioid receptors(s) of the central vs peripheral nervous systems. Thus, incorporation of conformational constraint in the putative 'address' segment of Dyn A analogs has resulted in the κ/μ opioid receptor ligands [L- Pen⁵,Cys¹¹]Dyn A_1-11-NH₂ (4), [Cys⁵,Cys¹⁰]Dyn A_1-11-NH₂ (5), [Cys⁵,Cys⁹]Dyn A_1-11-NH₂ (6), and [Cys⁴,Cys⁹,Arg¹⁰]Dyn A_1-11- NH₂ (7). All of these analogs possess high κ and μ opioid receptor affinities for the central receptor (guinea pig brain), but effect only weak potency at peripheral κ and μ opioid receptors (GPI). In fact cyclic dynorphin A analog 4 shows >19 000-fold differences between central κ opioid affinity and potency in the guinea pig ileum (GPI). Additionally analog 4 is not an antagonist in the GPI, suggesting possible receptor differences between these sites. Substitution of Tyr¹ by Phe¹ in the cyclic 1-11 series gave the analog [Phe¹,Cys⁵,Cys¹¹]Dyn A_1-11-NH₂ (1) that was surprisingly potent in the guinea pig brain binding assay (IC₅₀ = 15.1 nM) at the κ receptor, but was inactive in the GPI and mouse vas deferens bioassays. D-Ala² and Tic⁴ analogs of 1 had lower affinity at brain κ receptors and had very weak potencies in the GPI and MVD bioassays. On the other hand, [Cys⁶,Cys¹⁰]Dyn A_1-11-NH₂ (8), [Cys⁸,D-Cys¹³]Dyn A_{1- 13}-NH₂ (9), [D-Cys⁸,D-Cys¹²]Dyn A_1-13-NH₂ (10), and [D- Pro¹⁰,Cys⁵,Cys¹³]Dyn A_1-13-NH₂ (11) were surprisingly potent in the GPI bioassay, though considerable apparent selectivity for central receptors is still retained. The apparent lack of correlation between the pharmacological profiles observed in smooth muscle and in the brain binding assays, particularly with 1 and 4, may suggest the existence of different subtypes of the κ and μ opioid receptors in the brain and peripheral systems.