Felix E. Granchelli

On the ability of N-chloroethyl aporphine derivatives to cause irreversible inhibition of dopamine receptor mechanisms

The potential dopamine inhibitory properties of (‐)N‐(2‐chloroethyl)‐norapomorphine [(‐)NCA], (‐)N‐(hydroxyethyl)norapomorphine [(‐)NHA], (‐)N‐(2‐chloroethyl)‐norapocodeine[(‐)NCC] and 6‐[2‐bis‐(2‐chIoroethyl)‐amino]acetyl‐11‐acetoxy‐2‐hydroxy‐10‐methoxynoraporphine (I) were assessed in behavioural (ability to antagonize apomorphine climbing, stereotypy and circling after unilateral electrolesions of the striatum in the mouse, ability to initiate circling/asymmetry alone or after challenge with apomorphine when injected unilaterally into the striatum of rat) and biochemical (ability to inhibit the binding of [3H] (‐)N‐n‐propylnorapomorphine, 3H‐NPA, to rat striatal homogenates) tests. (‐) NCA, 10–20 mg kg−1 s.c., antagonized apomorphine climbing for a period of 5 days, the response recovering to control values by the 7th day. 10 mg kg−1 s.c. (‐)NHA, (‐)NCC or I failed to modify apomorphine climbing. Similarly, 2–4 mg kg−1 s.c. (‐)NCA caused a long‐lasting inhibition of apomorphine circling in the mouse (up to 5 days) whilst (‐)NHA, (‐)NCC and I were inactive. (‐)NCA (10–40 μg) (but not (‐)NHA, (‐)NCC or I) also caused ipsilateral circling/asymmetry when injected unilaterally into the striatum of rat: this effect was enhanced by apomorphine. However, all agents, including (‐)NCA, failed to consistently modify apomorphine stereotypy in the mouse. Non‐labelled (‐)NPA, (‐)NCA and (‐)NHA were shown to inhibit the ‘specific’ binding of 3H‐NPA to rat striatal homogenates; (‐)NCC and I were ineffective. A single washing removed the (‐)NHA inhibition whilst repeated washing caused only a modest reversal of the inhibition afforded by (‐)NCA. It is concluded that N‐chloroethylation in the aporphine series can abolish dopamine agonist action and confer a long‐lasting dopamine antagonist potential.

Sulfenylation and Halogenation of Di-and Trianions Derived from Substituted Glutarimides

Abstract In a program designed to synthesize and evaluate glutethimide derivatives 1 for antiprogestational activity1 we required a general method for introducing a variety of substituents at C-5. Traditional methods for functionalizing an α carbon of glutarimide derivatives involve (1) cyclization of an appropriately substituted acyclic precursor2, (2) imide bromination followed by SN2 delivery of the desired substituent3, or (3) generation of the dianion of the imide with an alkali amide in liquid ammonia and reaction with an electrophile4. The utilization of an intermediate dianion was prompted, in large measure, by limitations imposed by the first two methods, i.e., the large number of synthetic operations re-quired to prepare a series of highly functionalized acyclic precursors and the paucity of nucleophiles capable of displacing bromide without concomitant side reactions.