TY - JOUR
T1 - δ Opioid Antagonist Activity and Binding Studies of Regioisomeric Isothiocyanate Derivatives of Naltrindole
T2 - Evidence for δ Receptor Subtypes
AU - Portoghese, Philip S
AU - Sultana, M.
AU - Nelson, W. L.
AU - Klein, P.
AU - Takemori, A. E.
PY - 1992/10/1
Y1 - 1992/10/1
N2 - The isothiocyanate group was attached to the 4′-, 5′-, 6′-, or 7′-position of naltrindole in an effort to determine the importance of the position of this electrophilic group on the selectivity for subtypes of δ opioid receptors. All of the ligands were δ-selective when tested against standard agonists in smooth muscle preparations. However, the rank-order antagonism of δ antinociception in mice did not parallel the in vitro pharmacologic data. The 5′-isothiocyanate 2 was the most potent and selective antagonist in vivo, causing a 52-fold increase of the ED50 for [d-Ser2,d-Leu5]enkephalin-Thr6 (DSLET) and no increase for [d-Pen2,d-Pen5]enkephalin (DPDPE). The effect of each of the ligands on the binding of [3H]DSLET and [3H]DPDPE to guinea pig brain membranes clearly differentiated between the binding sites that recognize these radioligands. These studies provide additional evidence for the presence of two subtypes of δ opioid receptors.
AB - The isothiocyanate group was attached to the 4′-, 5′-, 6′-, or 7′-position of naltrindole in an effort to determine the importance of the position of this electrophilic group on the selectivity for subtypes of δ opioid receptors. All of the ligands were δ-selective when tested against standard agonists in smooth muscle preparations. However, the rank-order antagonism of δ antinociception in mice did not parallel the in vitro pharmacologic data. The 5′-isothiocyanate 2 was the most potent and selective antagonist in vivo, causing a 52-fold increase of the ED50 for [d-Ser2,d-Leu5]enkephalin-Thr6 (DSLET) and no increase for [d-Pen2,d-Pen5]enkephalin (DPDPE). The effect of each of the ligands on the binding of [3H]DSLET and [3H]DPDPE to guinea pig brain membranes clearly differentiated between the binding sites that recognize these radioligands. These studies provide additional evidence for the presence of two subtypes of δ opioid receptors.
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U2 - 10.1021/jm00100a014
DO - 10.1021/jm00100a014
M3 - Article
C2 - 1331455
AN - SCOPUS:0026540054
SN - 0022-2623
VL - 35
SP - 4086
EP - 4091
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 22
ER -
