Salvinorin A and derivatives: Protection from metabolism does not prolong short-term, whole-brain residence

Medical Department, Brookhaven National Laboratory, Upton, NY 11973, USA.
Neuropharmacology (Impact Factor: 5.11). 08/2009; 57(4):386-91. DOI: 10.1016/j.neuropharm.2009.06.044
Source: PubMed


Salvinorin A (SA) is a potent kappa opioid agonist with a brief duration of action. Consistent with this, our previous positron emission tomography (PET) studies of carbon-11 labeled SA showed that brain levels decrease rapidly after intravenous administration. SA is rapidly metabolized, giving the much less potent salvinorin B (SB), which is presumed to be responsible in part for SA's brief duration of action. To test this, we labeled the metabolically stable methyl ester of SA and SB with carbon-11 and compared their pharmacokinetics by PET imaging after intravenous administration to baboons. Labeling of salvinorin B ethoxymethyl ether (EOM-SB), a derivative with greater potency and resistance to metabolism, provided an additional test of the role of metabolism in brain efflux. Plasma analysis confirmed that SB and EOM-SB exhibited greater metabolic stability than SA. However, the three compounds exhibited very similar pharmacokinetics in brain, entering and exiting rapidly. This suggests that metabolism is not solely responsible for the brief brain residence time of SA. We determined that whole-brain concentrations of EOM-SB declined more slowly than SA after intraperitoneal administration in rodents. This is likely due to a combination in EOM-SB's increased metabolic stability and its decreased plasma protein affinity. Our results suggest that protecting salvinorin A derivatives from metabolism will prolong duration of action, but only when administered by routes giving slow absorption.

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    • "While SALA (0.1–1.0 mg/kg) significantly elevated brain stimulation reward thresholds in C57BL/6J mice at all doses tested (F 3, 18 = 14.5, p < 0.001; Figures 1C and S4), SALB (3.0– 17.0 mg/kg) failed to significantly elevate thresholds up to 17.0 mg/kg s.c. Given that SALB is apparently inert in vivo, and because of its outstanding pharmacokinetic and CNS penetrability properties (Hooker et al., 2009), we predicted that SALB would represent a suitable ligand for a new DREADD. "

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