McN-4612 is a noradrenaline-preferring serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI) developed by McNeil Laboratories in the 1980s.
Pharmacology Binding affinities (Ki) are reported to be the following (nM):
As can be seen nearly all of the Ki activity resides in a single optical antipode (or enantiomer). Hence, there is a good eudysmic ratio While McN-4612-Y does not function as a positive reinforcer, according to the reference it might possibly have utility as an antipsychotic. It appears alongside McN-4171, which is an analog of butaclamol.
Self-administration studies Although McN-4612 was never publicly taken by humans, the self-administration by rats is reported in the literature.
Analogs McN-4612 is the lead compound in a series of agents and the antecedent to such agents as McN5652, McN 5707, JNJ-7925476, Mcn-5292, McN-5558, McN-5908 or McN-5847 for example. The SAR can be manipulated to place particular emphasis on catecholaminergic neurotransmission or to incorporate 5-HT into the pharmacophore. Some of these compounds are tremendously powerful agents. At the time of discovery, McN-5908 was the most powerful psychostimulant ever discovered, although it was claimed that it was also quite toxic. Only a few of the phenyltropanes are believed to have potencies that can rival this agent.
Synthesis A number of methods are available to synthesizing these agents in the appendant literature. The first scheme relies on 2,2-diphenylethylamine, which itself is the product of the reduction of diphenylacetonitrile. However, the 2-phenylpyrrolidine route is also attractive. Recently, an enantiomerically selective method was reported using this method of synthesis. It is worth noting that this compound is itself made from 4-chlorobutyronitrile.
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