In vitro and in vivo characterization of a novel negative allosteric modulator of neuronal nAChRs
In this study, we compared the in vitro and in vivo neuronal nicotinic acetylcholine receptor (nAChR) properties of 1,2,3,3a,4,8b-hexahydro-2-benzyl-6-N,N-dimethylamino-1-methylindeno[1,2, -b]pyrrole (HDMP, 4) to that of negative allosteric modulator (NAM), PCP. Patch-clamp experiments showed that HDMP exhibited an inhibitory functional activity at alpha 7 nAChRs with an IC50 of 0.07 mu M, and was 357- and 414-fold less potent at alpha 4 beta 2 and alpha a3 beta 4 nAChRs, with IC(50)s of 25.1 and 29.0 mu M, respectively. Control patch-clamp experiments showed that PCP inhibited alpha 7, alpha 3 beta 2 and alpha 3 beta 4 nAChRs with IC(50)s of to 1.3, 29.0 and 6.4 mu M, respectively. Further, HDMP did not exhibit any appreciable binding affinity to either alpha 7 or alpha 4 beta 2 nAChRs, suggesting its action via a non-competitive mechanism at these neuronal nAChR subtypes. The in vivo study showed that HDMP was a potent antagonist of nicotine-induced analgesia in the tail-flick (AD(50) = 0.008 mg/kg), but not in the hot-plate test. All together, our in vitro and in vivo data suggest that HDMP is a novel NAM of neuronal nAChRs with potent inhibitory activity at alpha 7 nAChR subtype at concentrations <= 1 mu M that are not effective for MR and alpha 3 beta 4 nAChRs. (C) 2010 Elsevier Ltd. All rights reserved
Abdrakhmanova, G. R., Blough, B., Nesloney, C., Navarro, H., Damaj, M. I., & Carroll, F. (2010). In vitro and in vivo characterization of a novel negative allosteric modulator of neuronal nAChRs. Neuropharmacology, 59(6), 511-517.