Add time:07/30/2019         Source:sciencedirect.com

N-Methyl-N-[(1S)-1-(4-isophiocyanatophenyl)-2-(1-dyrrolidinyl)ethyl-3,4-dichlorophenylacetamide (MITPD)1, is an isothiocyanate derivative of the κ agonist ICI-199,441. In this study, interaction of MITPD with cloned μ, δ, and κ opioid receptors was characterized. MITPD inhibited [3H]diprenorphine binding to κ receptors with high affinity and with ~700- and ~870-fold selectivity over μ and δ receptors. Pretreatment with MITPD followed by extensive washing reduced κ receptor binding with an IC50 value of 3.7 nM, but did not affect μ or δ binding at ≤ 0.1 μM. Preincubation with 1 μM MITPD abolished [3H]diprenorphine binding, while pretreatment with 1 μM ICI-199,441 increased Kd of [3H]diprenorphine binding with no change in Bmax. Thus, MITPD is a selective κ irreversible ligand. The region of the κ receptor that conferred selectivity for MITPD was determined by examining its binding to four μκ chimeras. IC50 values of MITPD for inhibition of [3H]diprenorphine binding were determined to be 430 nM for Chimera III (κ1−141μ151−398), 1.8 nM for Chimera IV (μ1−150κ142−380), 40 nM for Chimera XI (μ1−268κ263−380) and 14 nM for Chimera XII (κ1−262μ269−398). Pretreatment with MITPD followed by extensive washing reduced binding to chimera IV with an IC50 value of 75 nM, but did not affect III, XI or XII binding (IC50 ⪢1 μM). Thus, the region from the third transmembrane helix to the C-terminus of the κ receptor is important for the binding of MITPD.

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