Abstract
2-, 3-, and 4-iodophenyl derivatives of the high-affinity σ ligand N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine (1) were synthesized in two to four steps starting from N-methyl-2-(1-pyrrolidinyl)ethylamine. These compounds were evaluated for their capacity to label both σ1 and σ2 subtypes in vitro. σ-1 binding affinity was determined by measuring competition with [3H]-(+)-pentazocine binding to guinea pig brain membranes while σ2 binding was evaluated through competition with [3H]DTG binding to rat liver membranes in the presence of excess dextrallorphan. The binding data revealed that N-[2-(3-iodophenyl)ethyl]-N-methyl-2-(1-pyrrohdinyl)ethylamine (2) and N-[2-(4-iodophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine (3) displayed almost identical binding affinity at σ1 sites to the parent compound 1. This suggests that the 3- or 4-iodo group can effectively substitute for the 3,4-dichloro substituents of 1. In this series of compounds, Ki's at the σ1 site varied from 2.0 nM for N-(4-iodobenzyl)-N-methyl-2-(1-pyrrolidinyl)ethylamine (6) to 26.6 nM for N-(2-iodobenzyl)-N-methyl-2-(1-pyrrolidinyl)ethylamine (4). Ki's for σ2 site ranged from 8.1 nM for 1 to 220 nM for N-(3-bromobenzyl)-N-methyl-2-(1-pyrrolidinyl)ethylamine (11) while the σ2/σ1 ratio varied from 1.8 for 4 to 25 for 11. Comparing halogen substitution, the trend Cl = I > Br > F was observed for binding affinity at σ1 sites; no such trend was observed at σ2 sites. On the basis of the binding data, compounds 2 and 3 were selected for labeling with 123I. Thus, treatment of the corresponding 3- and 4-(tributylstannyl) intermediates (7 and 8) with Na123I in the presence of excess CH3CO3H furnished [123I]-2 and [123I]-3 in up to 70% radiochemical yield. Preliminary in vitro binding with [123I]-3 indicated up to 97% specific binding with guinea pig brain membranes.
Original language | English (US) |
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Pages (from-to) | 566-571 |
Number of pages | 6 |
Journal | Journal of medicinal chemistry |
Volume | 36 |
Issue number | 5 |
DOIs | |
State | Published - Jan 1 1993 |
Externally published | Yes |
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery