For several years in BI(g) Pharma, I was responsible for determining how ongoing changes in US legislation on controlled substances affected the screening collection. The following came about from thoughts on the legal definition of 'positional isomer' and how to identify structures that might fall under that definition. It is based on a manuscript that was approved for publication, but didn't make it into print.
Identification of Positional Isomers subject to US controlled substance legislation
In the course of developing a computational tool to flag structures that could be covered under the US legislation on controlled substances we were challenged by the definition provided for positional isomers.1
‘As used in Sec. 1308.11(d) of this chapter, the term "positional isomer" means any substance possessing the same molecular formula and core structure and having the same functional group(s) and/ or substituent(s) as those found in the respective schedule I hallucinogen, attached at any position(s) on the core structure, but in such manner that no new chemical functionalities are created and no existing chemical functionalities are destroyed relative to the respective schedule I hallucinogen. Rearrangements of alkyl moieties within or between functional group(s) or substituent(s), or divisions or combinations of alkyl moieties, that do not create new chemical functionalities or destroy existing chemical functionalities, are allowed i.e., result in compounds which are positional isomers. For purposes of this definition, the "core structure" is the parent molecule that is the common basis for the class; for example, tryptamine, phenethylamine, or ergoline. Examples of rearrangements resulting in creation and/or destruction of chemical functionalities (and therefore resulting in compounds which are not positional isomers) include, but are not limited to: ethoxy to alpha-hydroxyethyl, hydroxy and methyl to methoxy, or the repositioning of a phenolic or alcoholic hydroxy group to create a hydroxyamine. Examples of rearrangements resulting in compounds which would be positional isomers include: tert- butyl to sec-butyl, methoxy and ethyl to isopropoxy, N,N-diethyl to N- methyl-N-propyl, or alpha-methylamino to N-methylamino.’
The definition is narrower than the IUPAC definition of isomer2 ‘One of several species (or molecular entities) that have the same atomic composition (molecular formula) but different line formulae or different stereochemical formulae and hence different physical and/or chemical properties’. It is broader than the simplest interpretation of positional isomers as species with the same functional groups attached to different positions on the same chain or scaffold. The definition is relevant to some sixty eight substances covered in Schedule 1 (d), an additional five substances temporarily listed in Schedule I, four substances in Schedule III and one substance in Schedule IV as of 3/14/2017.3
The concept that a query structure should match a target where alkyl groups have been split, possibly recombined and reattached to a core complicates any computational matching process. As an example, in Figure 2, for the controlled substance, 2,5-dimethoxy-4-(n)-propylthiophenethylamine (1) whose positional isomers are also controlled,3 the propylthio group can be deconstructed to an ethylthio group with the residual carbon reattached anywhere to the molecule as a methyl group as in 2, or to a methylthio group with the residual two carbons reattached as an ethyl or two methyl substituents as in 3. Compounds 2 and 3 are two example positional isomers of 1 out of a possible sixty one that are consistent with the definition.