Semisynthesis of Salvinicins A & B

Harding et al. synthesised Salvinicins A & B from Salvinorin in two steps. Although the total synthesis of Salvinorin is still not published this work is very interesting as Salvinorin is a kappa opioid receptor agonist while the authors found that another compound derived from salvinorin in few steps is a delta opioid receptor antagonist.

Original article:
J. Nat. Prod.; 2006; 69(1) pp 107 - 112
http://dx.doi.org/10.1021/np050398i

A group of scientist from Hungary and Austria investigated the binding of MDMA synthesis byproducts to the pharmaclogical target of MDMA, the human serotonin transporter. Two compounds inhibited the release of serotonin which is the primary effect of MDMA. These compounds 1,3-bis(3,4-methylenedioxyphenyl)-2-propanamine and N-formyl-1,3-bis (3,4-methylenedioxyphenyl)-prop-2-yl-amine are synthesis byproducts when MDMA resp. MDA is synthesized from piperonal. All other tested byproducts had no relevant affinity to the monoamine transporter. According to the data from the article it is not very likely that synthesis byproducts are responsible for the toxicity of ecstasy.

Original article: http://dx.doi.org/10.1124/jpet.105.084426.

Paroxetine increases blood levels of MDMA

In Clin. Pharmacokinet., 2005, 44(6), 649-660 de la Torre et al gave the antidepressive drug paroxetine (Paxil and other trade names) prior to MDMA consumption. Paroxetine inhibits the CYP2D6 enzyme which is responsible for MDMA metabolism. The authors conclude that CYP2D6 is responsible for less than 30% of the MDMA metabolism.
The combination of paroxetine and MDMA increased the total blood level (AUC) of MDMA and increased the maximum concentration (cmax) while decreasing the amount of the primary metabolite HMMA. The time until the maximum concentration (tmax) is not changed. The elimination of MDMA (ke) is decreased compared to MDMA and placebo.
The authors conclude that CYP2D6 polymorphism is less likely to be linked to MDMA toxicity as MDMA is still metabolised to HMMA by other, unknown enzymes.

Some comments on metabolism and pharmacokinetics of MDMA (Ecstasy)

A research group from Spain investigated the influence of a polymorphism of a liver enzyme (CYP2D6) on the pharmacokinetics of MDMA. Approximately 10% of the european caucasian population are so called 'poor metabolisers' which means that their CYP2D6 enzyme is working slower. MDMA is metabolised by the CYP2D6 enzyme. As MDMA toxicity is related to MDMA blood levels it may be that a part of the population is especially sensitive to MDMA. The metabolism of the CYP2D6 poor metaboliser was slower, resulting in higher MDMA concentrations in blood.

Original article: http://dx.doi.org/10.1007/s00228-005-0965-y