The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Mar 2004
Salvinorin A, an active component of the hallucinogenic sage salvia divinorum is a highly efficacious kappa-opioid receptor agonist: structural and functional considerations.
The diterpene salvinorin A from Salvia divinorum has recently been reported to be a high-affinity and selective kappa-opioid receptor agonist (Roth et al., 2002). Salvinorin A and selected derivatives were found to be potent and efficacious agonists in several measures of agonist activity using cloned human kappa-opioid receptors expressed in human embryonic kidney-293 cells. Thus, salvinorin A, salvinorinyl-2-propionate, and salvinorinyl-2-heptanoate were found to be either full (salvinorin A) or partial (2-propionate, 2-heptanoate) agonists for inhibition of forskolin-stimulated cAMP production. ⋯ Because issues of receptor reserve complicate estimates of agonist efficacy and potency, we also examined the agonist actions of salvinorin A by measuring potassium conductance through G protein-gated K(+) channels coexpressed in Xenopus oocytes, a system in which receptor reserve is minimal. Salvinorin A was found to be a full agonist, being significantly more efficacious than (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide methane-sulfonate hydrate (U50488) or (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide methane-sulfonate hydrate (U69593) (two standard kappa-opioid agonists) and similar in efficacy to dynorphin A (the naturally occurring peptide ligand for kappa-opioid receptors). Salvinorin A thus represents the first known naturally occurring non-nitrogenous full agonist at kappa-opioid receptors.
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J. Pharmacol. Exp. Ther. · Mar 2004
The distribution of the HIV protease inhibitor, ritonavir, to the brain, cerebrospinal fluid, and choroid plexuses of the guinea pig.
Anti-human immunodeficiency virus (HIV) drug penetration into the brain and cerebrospinal fluid (CSF) is necessary to tackle HIV within the CNS. This study examines movement of [(3)H]ritonavir across the guinea pig blood-brain and blood-CSF barriers and accumulation within the brain, CSF, and choroid plexus. Ritonavir is a protease inhibitor, used in combination therapy (often as a pharmacoenhancer) to treat HIV. ⋯ Additionally, the involvement of transporters on [(3)H]ritonavir passage across the brain barriers was assessed. Results from in situ brain perfusions and capillary depletion analysis demonstrated that [(3)H]ritonavir uptake into the guinea pig brain was considerable (6.6 +/- 0.7 ml/100 g at 30 min, vascular space corrected), although a proportion of drug remained trapped in the cerebral capillaries and did not reach the brain parenchyma. CSF uptake was more limited (2.2 +/- 0.4 ml/100 g at 30 min), but choroid plexus uptake was abundant (176.7 +/- 46.3 ml/100 g at 30 min). [(3)H]Ritonavir brain and CSF uptake was unaffected by neither inhibitors of organic anion transport (probenecid and digoxin) or P-glycoprotein (progesterone), nor by any additional anti-HIV drugs, indicating that brain barrier efflux systems do not significantly limit brain or CSF [(3)H]ritonavir accumulation in this model. [(3)H]Ritonavir uptake into the perfused choroid plexus was significantly reduced by nevirapine and abacavir, additional perfusion studies, and isolated incubated choroid plexus experiments were carried out in an attempt to further characterize the transporter involved.