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\begin{document}

\title{Inhibition of HCN1 currents by norquetiapine, an active metabolite of
the atypical anti-psychotic drug quetiapine}



\author[1]{Nazzareno D'Avanzo}%
\author[1]{Amélie Jean Jacques}%
\affil[1]{Université de Montréal}%


\vspace{-1em}



  
  \date{May 21, 2024}


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\begin{abstract}
Background and Purpose Quetiapine is a second-generation atypical
antipsychotic drug that has been commonly prescribed for the treatment
of schizophrenia, major depressive disorder (depression), and other
psychological disorders. Targeted inhibition of
hyperpolarization-activated cyclic-nucleotide gated (HCN) channels,
which generate Ih, may provide effective resistance against
schizophrenia and depression. We investigated if HCN channels could
contribute to the therapeutic effect of quetiapine, and its major active
metabolite norquetiapine. Experimental Approach Two-electrode voltage
clamp recordings were used to assess the effects of quetiapine and
norquetiapine on currents from wild-type and mutant HCN1 and HCN2
expressed in Xenopus laevis oocytes. Key Results Norquetiapine, but not
quetiapine nor 7-hydroxy quetiapine, has an inhibitory effect on HCN1
channels. Norquetiapine selectively inhibited HCN1 currents by shifting
the voltage-dependence of activation to more hyperpolarized potentials
in a concentration-dependent manner with an IC50 of 13.9 \selectlanguage{ngerman}± 0.8 \selectlanguage{greek}μ\selectlanguage{english}M for
HCN1 and slowing channel opening, without changing the kinetics of
closing. Inhibition by norquetiapine primarily occurs from in the closed
state. Norquetiapine inhibition is not sensitive to the external
potassium concentration, and therefore, likely does not block the pore.
Norquetiapine inhibition also does not dependent on the
cyclic-nucleotide binding domain. Norquetiapine had no effect on HCN2
channels. Conclusions and Implications HCN channels are key targets of
norquetiapine, the primary active metabolite of quetiapine. These data
help to explain the therapeutic mechanisms by which quetiapine aids in
the treatment of anxiety, major depressive disorder, bipolar disorder,
and schizophrenia, and may represent a novel structure for future drug
design of HCN inhibitors.%
\end{abstract}%



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