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Fig. 2. Synthesized peptides and (A) Inhibition of [ 125 I]Epibatidine binding toimmunoimmobilised striatal α6β2* receptors induced by native PIA, ∆R-PIA, ∆RD-PIAand ∆RDP-PIA peptides; (B)Affinity of [E11R]MII and [E11R]RDP-MII peptides forα6β2*; (C) affinity of [E11R]MII and [E11R]RDP-MII peptides for the native α3β2*.affected at the α3β2* subtype (Figure 2C). Unlike PIA, MII also binds the α3β2 subtypewith relatively high affinity, and molecular modeling investigations showed that theglutamic acid (E) residue in position 11 plays a primary role in piloting molecularrecognition. We therefore designed and synthesised new analogues of MII in which E11was replaced by R [i.e., (E11R)MII and (E11R)RDP-MII)], and found that they displayedthe same potency and affinity for native rat α6β2* as MII and RDP-MII (Figure 2B), butlower affinity and potency for the native and heterologously expressed α3β2* subtype(Figure 2C). Hence, the novel (E11R)MII and (E11R)RDP-MII peptides are potent andselective α6β2* antagonists.In conclusion, we designed and synthesised new analogues of MII in which E11 wasreplaced by R (i.e., [E11R]MII and [E11R]RDP-MII), and found that they displayed a) thesame potency and affinity for native rat α6β2* nAChRs as MII and RDP-MII, and b) loweraffinity and potency for the native and heterologously expressed α3β2* subtype. Hence, thenovel [E11R]MII and [E11R]RDP-MII peptides are potent and selective α6β2* vs. α3β2*antagonists.AcknowledgmentsThis study was financially supported by the Italian research grants: FIRB # RBNE03FH5Y002 andPRIN # 20072BTSR2References1. Gotti, C., Zoli, M., Clementi, F. Trends Pharmacol. Sci. 27, 482-491 (2006).2. Gotti, C., et al. Biochem. Pharmacol. 78, 703-711 (2009).3. Olivera, B.C., et al. Channels (Austin) 2, 143-152 (2008).575