Received for publication October 18, 2007.
Revised February 14, 2008.
Accepted for publication February 15, 2008.

Preclinical characterization of selective PDE10A inhibitors: A new therapeutic approach to the treatment of schizophrenia

Abstract

We have recently proposed the hypothesis that inhibition of the cyclic nucleotide phosphodiesterase, PDE10A, may represent a new pharmacological approach to the treatment of schizophrenia (Menniti et al., 2007). PDE10A is highly expressed in the medium spiny neurons of the mammalian striatum (Seeger et al., 2003; Xie et al, 2006, Coskran et al, 2006) where the enzyme is hypothesized to regulate both cAMP and cGMP signaling cascades to impact early signal processing in the corticostriatothalamic circuit (Siuciak et al, 2006a; Siuciak et al, 2006b; Strick et al, 2006). Our current understanding of the physiological role of PDE10A and the therapeutic utility of PDE10A inhibitors derive in part from studies with papaverine, the only pharmacological tool for this target extensively profiled to date. However, this agent has significant limitations in this regard, namely, relatively poor potency and selectivity and a very short exposure half life after systemic administration. In the present report, we describe the discovery of a new class of PDE10A inhibitors exemplified by TP-10, an agent with greatly improved potency, selectivity and pharmaceutical properties. These new pharmacological tools enabled studies that provide further evidence that inhibition of PDE10A represents an important new target for the treatment of schizophrenia and related disorders of basal ganglia function.

Key words: antipsychotic, cAMP, cGMP, phosphodiesterase, schizophrenia, striatum