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Potential antipsychotic agents. Part 8 . Antidopaminergic properties of a potent series of 5‐substituted (−)‐( S )‐ N ‐[(1‐ethylpyrrolidin‐2‐yl)methyl]‐2,3‐dimethoxybcnzaimides. Synthesis via common lithio intermediates
Author(s) -
Högberg Thomas,
Ström Peter,
Hall Håkan,
Ögren Sven Ove
Publication year - 1990
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.19900730221
Subject(s) - chemistry , raclopride , stereochemistry , spiperone , electrophile , apomorphine , trimethylsilyl , radioligand , steric effects , bicyclic molecule , haloperidol , in vivo , medicinal chemistry , dopamine , receptor , dopamine receptor d2 , dopamine receptor , organic chemistry , biochemistry , microbiology and biotechnology , neuroscience , catalysis , biology , agonist
A series of 5‐substituted (−)‐( S )‐ N ‐[(1‐ethylpyrrolidin‐2‐yl)methyl]‐2,3‐diniethoxybenzanndes were made by reaction of the corresponding benzoyl chlorides with ( S )‐1‐ethylpyrrolidine‐2‐methylaruine (→ 14–16 , 18–21 ). The acids required were prepared in a regiospecific manner from 5‐bromo‐2,3‐dimethoxybenzoic acid which was protected as dihydrooxazole (→ 4–8 ), metalated, reacted with various electrophiles (MeI, EtI, BuBr, CC1 3 CCl 3 or MeSSMe), and hydrolyzed (→ 9–13 ). Alternatively, (‐)‐( S )‐5‐bromo‐ N ‐[(1‐ethylpyrrolidin‐2‐yl)methyl]‐2,3‐di‐methoxybenzamide was treated with KH followed by BuLi and an electrophile (I 2 or Me 3 SiCl) to give the 5‐iodo and 5‐(trimethylsilyl) derivatives 17 and 22 , respectively. All 5‐substituted amides were highly potent inhibitors of [ 3 H]spiperone binding in rat striatal membranes with IC 50 values of 0.5 to 5 nM ( Table 3 ). Thus, a relatively large steric bulk can be accomodated in the position para to the 2‐MeO group. This work also supports the notion that a positive as well as negative electrostatic potential can be located in this position. A selected number of derivatives were also investigated in vivo and found to inhibit apomorphine‐induced behavioural responses in the same dose range as haloperidol and raclopride ( Table 4 ). This new group of benzamides is suitable for investigations of dopamine D‐2 receptors in labelled or unlabelled form.