[Pro³]Dyn A(1−11)-NH₂:  A Dynorphin Analogue with High Selectivity for the κ Opioid Receptor

Abstract

A proline scan at positions 2 and 3 of the opioid peptide dynorphin A(1-11)-NH(2) led to the discovery of the analogue [Pro(3)]Dyn A(1-11)-NH(2). This analogue possesses high affinity and selectivity for the kappa opioid receptor (K(i)(kappa) = 2.7 nM, K(i) ratio kappa/micro/delta = 1/2110/3260). The gain in selectivity is achieved through an overall reduction of opioid receptor affinity which is most pronounced at micro and delta receptors. The Pro(3) analogue exhibits antagonist properties. Despite its high kappa affinity, [Pro(3)]Dyn A(1-11)-NH(2) is a relatively weak antagonist in both the [(35)S]GTPgammaS assay (IC(50) = 380 nM) and the guinea pig ileum assay (K(e) = 244 nM). Discrepancies between GPI and binding assay have often been ascribed to differential kappa receptor subtypes prevailing in central vs peripheral neurons. Since the [(35)S]GTPgammaS assay uses the same membrane preparations as the binding assay, differential kappa subtypes can be ruled out as an explanation in this case, and the observed behavior rather seems to reflect an intrinsic property of the ligand.

Dynorphin a Analogs for the Treatment of Chronic Neuropathic Pain

“…This substitution did cause antagonism at all three opioid receptors, but the selectivity for KOR was reduced (KOR/MOR/DOR = 1/0.5/0.14, Table 4) [60]. The Schiller group designed (2′,6′-dimethyltyrosine [Dmt] 1 ) Dyn A-(1-11)NH 2 analogs with the N-terminal amino group deleted or replaced with a methyl group using Table 4) but is a weak antagonist in both the GPI assay as well as the ( 35 S)GTPγS assay [62]. Aldrich and colleagues identified aromatic dynorphin (arodyn) starting from a novel chimeric peptide, extacet (a MOR-selective analog), substituted at the N-terminus in the message region.…”

“…1/260/200 3.9 ± 0.7 [61] [Pro 3 ] DynA-(1-11)NH 2 H-Y-G-P-F-L-R-R-I-R-P-K-NH 2 1/2100/3300 240 ± 51 [62] Arodyn Ac-F-F-F-R-L-R-R-a-R-P-K-NH 2 1/170/580 N.D.…”

Tyrosine and peptide reorientational mobility in polymer solutions: Time‐dependent fluorescence anisotropy measurements

“…thermal coefficient of friction following the approach described previously. 7 The temperature dependence of the viscosity over the relevant temperature range can be described by 18 ln ϭ Ϫ b ͑T Ϫ T 0 ͒ ϩ ln 0 (1) where is the viscosity at temperature T, 0 is the viscosity at temperature T 0 , and b is the thermal coefficient of friction associated with the viscosity. For rotational diffusion in the hydrodynamic limit, the rotational correlation time depends on temperature and viscosity in a manner described by the StokesEinstein-Debye equation.…”

“…1,2 The activity of such peptides is closely linked not only to their structure but also to their dynamic properties. These include the rate at which a peptide samples the available conformational space and the stability of structural features such as reverse turns.…”

Deletion of Ac‐NMePhe1 from [NMePhe1]arodyn under acidic conditions, part 2: Effects of substitutions on pharmacological activity

“…Early analogs generally exhibited weak antagonist activity and low κ opioid receptor selectivity, but recently more selective and potent analogs have been reported. [Pro 3 ]Dyn A-(1-11)NH 2 has high affinity and selectivity (K i ratio (κ/μ/δ) = 1/2110/3260) for κ opioid receptors, but this ligand exhibits only weak antagonist potency in functional assays 23. Its Arg8 analog shows higher κ affinity without compromising the high κ selectivity 24.…”