Rapid Illicit Drug Development and Characterization

Analogs of controlled substances are a major source of disagreement in the legal community. The analog statute of the Controlled Substances Act criminalizes any analog which has a structure or effect that is “substantially similar” to a scheduled drug.  This vague terminology allows for much debate in a courtroom – what is “substantially similar”?  In the justice system, conviction or acquittal in cases of analogs of scheduled drugs often comes down to the testimony of a scientist on similarity of structure or efficacy.  Comparison of structures can be problematic because opinions differ on what qualifies as “similar enough.”
To circumvent this problem, one-pot synthesis techniques are being developed which will provide mixed products of many potential drug analogs for characterization in a more meaningful way.  These potential analogs are structurally characterized via electrospray ionization – mass spectrometry and collision induced dissociation (CID) prior to further investigation of their effectiveness as drugs.  The structures and fragmentation patterns are then entered into a searchable database (ACD Labs) which could potentially be adapted for a web portal available for criminal investigation labs.
By using a parallel artificial membrane permeability assay for the blood-brain barrier (PAMPA-BBB), the BBB permeability of these synthesized compounds can be determined.  By using two 96-well plates sandwiched together and separated by porous PVDF membranes coated in a phospholipid mixture, drug diffusion from the top well to the bottom well is measured by dilution and ESI-MS analysis.  This is valuable information to have because psychedelic or mind-altering drugs must access receptors in the brain in order to behave similarly to currently scheduled drugs. 

If the substance can cross the BBB, receptor affinity can then be determined using cell membrane chromatography – mass spectrometry (CMC-MS), which uses homogenized rat brain membranes immobilized onto silica in a 50 mm x 2.1 mm stainless steel column.  Since receptors with which illicit drugs interact are often membrane bound (5-HT2a serotonin receptor, for instance), column retention is a good indication of receptor affinity of the synthesized potential analogs which are capable of crossing the BBB.