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In the recent article on alpha7 selective nicotinic agonists (Mazurov et al., Curr. Med. Chem. 2006, 13, 1567-1584) results from several recent studies on the pharmacological properties of the alpha7 agonist GTS-21 were not cited; three assertions made there consequently need to be clarified and modified.

First, it was stated that GTS-21 “failed to show a satisfactory pharmacokinetic profile in the areas of bioavailability and brain permeability” (last paragraph of page 6). Only one bioavailability study was cited (Briggs et al., 1997. Pharmacol. Biochem. Behavior 57:231-241). In that study bioavailability was estimated as 1% based on three cynomolgus monkeys that were administered a very low dose of GTS-21. Plasma levels of GTS-21 in only one of the three animals were detectable by HPLC. A number of other bioavailability studies have been reported. GTS-21 bioavailability estimates for rats not cited in the review article were 14% (Tatsumi et al., 2005. J. Med. Chem. 48:2678-2686), 19% (Mahnir et al., 1998. Biopharm. Drug Dispos. 19:147-151), and 23% (Azuma et al., 1999. Xenobiotica 29:747-762). The bioavailability of GTS-21 in the dog was estimated as 27% (Azuma et al., 2002. Drug Metab. Pharmacokinet. 17: 75-82). While bioavailability has not yet been measured in humans, peak plasma levels during clinical tests (Kitagawa et al., 2003. Neuropsychopharmacol. 28:542-551) were similar to those found in the rat and dog studies mentioned above. Thus, the very low monkey bioavailability estimate is not predictive of bioavailability for other mammalian species and bioavailability of GTS-21 is not unusually low for a drug.

Second, with regard to the brain permeability, GTS-21 has a very high octanol:water partition coefficient (3,810) and readily enters the brain (Mahnir et al., 1998; Kem et al., 2004. Mol. Pharmacol. 65:56-67; Kem et al., 2005. Soc. Neurosci. Mtg Abstr. 296.23). There are two published estimates of the brain/plasma ratio: <0.3 (Tatsumi et al., 2005. J. Med. Chem. 48:2678-2686; determined by undescribed methods) and 2.4 (Kem et al., 2005. Soc. Neurosci. Mtg Abstr. 296.23; determined by LC-MS analysis of microdialysis samples using an internal standard). A brain: blood ratio of 3.4 was previously reported (Kem et al., 2004. Mol. Pharmacol. 65:56-67; HPLC detection with an internal standard). Thus, GTS-21 appears to display excellent brain permeability.

Third, we wish to make a final point concerning the estimation of alpha7 nicotinic receptor selectivity. GTS-21 is remarkably selective in its ability to stimulate only the alpha7 nAChR subtype (deFiebre et al., 1995. Mol. Pharm. 47:164- 171; Meyer et al., 1997. Brain Res. 768:49-56). The review article states that the affinity of GTS-21 for the human alpha4- beta2 receptor is actually 100-fold higher than for the alpha7 receptor, based on the Briggs et al. paper. This statement needs to be qualified because the radioligand (cytisine) used in their radioligand binding experiments is well known to desensitize the alpha4-beta2 receptor and this enhances the affinity of a displacing ligand for this particular nicotinic receptor. In vitro receptor binding selectivity measurements utilizing this radioligand are unable to quantitatively predict clinical concentrations that would cause adverse effects that would likely be mediated by inhibiting the resting form of this receptor. Functional (electrophysiological) experiments indicate that even 3 micromolar GTS-21 does not inhibit the response of resting human alpha4-beta2 receptors to acetylcholine (Kem et al., 2004 paper cited above). This concentration exceeds by more than two orders of magnitude the 20 nM Ki of GTS-21 for the human alpha4-beta2 receptor estimated by its ability to displace tritiated cytisine (Briggs et al., 1994). In the published preclinical and clinical studies GTS-21 was administered orally or intraperitoneally and the plasma levels never exceeded 0.5 micromolar. Thus, inhibition of alpha4-beta2 receptors in the whole animal under these conditions is unlikely to have been significant. It seems that estimation of clinically relevant nAChR selectivity is best assessed by functional measurements rather than by binding experiments using desensitizing radioligands.
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Document Type: Research Article

Affiliations: Department of Pharmacology and Therapeutics University of Florida College of Medicine Gainesville Florida 32610-0267,USA.

Publication date: 2007-06-01

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