In vitro and in vivo characterization of a novel negative allosteric modulator of neuronal nAChRs.
Neuropharmacology 2010 Jul 12; In press
Abdrakhmanova G GR, Blough B BE, Nesloney C, Navarro H HA, Damaj M MI, Ivy Carroll F
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, 23298.
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 alpha7 nAChRs with an IC(50) of 0.07 muM, and was 357- and 414-fold less potent at alpha4beta2 and alpha3beta4 nAChRs, with IC(50)s of 25.1 and 29.0 muM, respectively. Control patch-clamp experiments showed that PCP inhibited alpha7, alpha4beta2 and alpha3beta4 nAChRs with IC(50)s of to 1.3, 29.0 and 6.4 muM, respectively. Further, HDMP did not exhibit any appreciable binding affinity to either alpha7 or alpha4beta2 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 alpha7 nAChR subtype at concentrations </= 1 muM that are not effective for alpha4beta2 and alpha3beta4 nAChRs.