Distinct profiles of α7 nAChR positive allosteric modulation revealed by structurally diverse chemotypes

Selective modulation of alpha 7 nicotinic acetylcholine receptors ( nAChRs) is thought to regulate processes impaired in schizophrenia, Alzheimer's disease, and other dementias. One approach to target alpha 7 nAChRs is by positive allosteric modulation. Structurally diverse compounds, including PNU120596, 4- naphthalene- 1- yl- 3a, 4,5,9b- tetrahydro- 3- H- cyclopenta[ c] quinoline- 8- sulfonic acid amide ( TQS), and 5- hydroxyindole ( 5- HI) have been identified as positive allosteric modulators ( PAMs), but their receptor interactions and pharmacological profiles remain to be fully elucidated. In this study, we investigated interactions of these compounds at human 7 nAChRs, expressed in Xenopus laevis oocytes, along with genistein, a tyrosine kinase inhibitor. Genistein was found to function as a PAM. Two types of PAM profiles were observed. 5- HI and genistein predominantly affected the apparent peak current ( type I) whereas PNU- 120596 and TQS increased the apparent peak current and evoked a distinct weakly decaying current ( type II). Concentrationresponses to agonists [ ACh, 3-[( 3E)- 3-[( 2,4- dimethoxyphenyl) methylidene]- 5,6- dihydro- 4H- pyridin- 2- yl] pyridine dihydrochloride ( GTS- 21), and N-[( 3R)- 1- azabicyclo[ 2.2.2] oct- 3yl]- 4- chlorobenzamide hydrochloride ( PNU- 282987)] were potentiated by both types, although type II PAMs had greater effects. When applied after alpha 7 nAChRs were desensitized, type II, but not type I, PAMs could reactivate alpha 7 currents. Both types of PAMs also increased the ACh- evoked alpha 7 window currents, with type II PAMs generally showing larger potentiation. None of the PAMs tested increased nicotineevoked Ca2+ transients in human embryonic kidney 293 cells expressing human alpha 4 beta 2 or alpha 3 beta 4 nAChRs, although some inhibition was noted for 5- HI, genistein, and TQS. In summary, our studies reveal two distinct alpha 7 PAM profiles, which could offer unique opportunities for modulating alpha 7 nAChRs in vivo and in the development of novel therapeutics for central nervous system indications.