Biochemical and behavioral effects of PDE10A inhibitors: Relationship to target site occupancy

Phosphodiesterase 10A (PDE10A) inhibitors increase the functionality of striatal medium spiny neurons and produce antipsychotic-like effects in rodents by blocking PDE10A mediated hydrolysis of cAMP and/or cGMP. In the current study, we characterized a radiolabeled PDE10A inhibitor, [3H]BMS-843496, and developed an ex vivo PDE10 binding autoradiographic assay to explore the relationship between PDE10 binding site occupancy and the observed biochemical and behavioral effects of PDE10 inhibitors in mice. [3H]BMS-843496 is a potent PDE10A inhibitor with a binding affinity (KD) of 0.15 nM and a functional selectivity of \u3e100-fold over other PDE subtypes tested. Specific [3H]BMS-843496 binding sites were dominant in the basal ganglia, especially the striatum, with low to moderate binding in the cortical and hippocampal areas, of the mouse and monkey brain. Systemic administration of PDE10 inhibitors produced a dose- and plasma/brain concentration-dependent increase in PDE10A occupancy measured in the striatum. PDE10A occupancy was positively correlated with striatal pCREB expression levels. PDE10A occupancy was also correlated with antipsychotic-like effects measured using the conditioned avoidance response model; a minimum of ∼40% occupancy was typically required to achieve efficacy. In contrast, a clear relationship between PDE10A occupancy and catalepsy scores, a potential extrapyramidal symptom readout in rodent, was not evident

BMS-933043, a Selective α7 nAChR Partial Agonist for the Treatment of Cognitive Deficits Associated with Schizophrenia

The therapeutic treatment of negative symptoms and cognitive dysfunction associated with schizophrenia is a significant unmet medical need. Preclinical literature indicates that α7 neuronal nicotinic acetylcholine (nACh) receptor agonists may provide an effective approach to treating cognitive dysfunction in schizophrenia. We report herein the discovery and evaluation of <b>1c</b> (BMS-933043), a novel and potent α7 nACh receptor partial agonist with high selectivity against other nicotinic acetylcholine receptor subtypes (>100-fold) and the 5-HT_3A receptor (>300-fold). <i>In vivo</i> activity was demonstrated in a preclinical model of cognitive impairment, mouse novel object recognition. BMS-933043 has completed Phase I clinical trials

Design and Synthesis of a New Series of 4‑Heteroarylamino-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octanes as α7 Nicotinic Receptor Agonists. 1. Development of Pharmacophore and Early Structure–Activity Relationship

The design and synthesis of a series of quinuclidine-containing spirooxazolidines (“spiroimidates”) and their utility as α7 nicotinic acetylcholine receptor partial agonists are described. Selected members of the series demonstrated excellent selectivity for α7 over the highly homologous 5-HT_3A receptor. Modification of the <i>N</i>-spiroimidate heterocycle substituent led to (1<i>S</i>,2<i>R</i>,4<i>S</i>)-<i>N</i>-isoquinolin-3-yl)-4′<i>H</i>-4-azaspiro­[bicyclo­[2.2.2]­octane-2,5′oxazol]-2′-amine (BMS-902483), a potent α7 partial agonist, which improved cognition in preclinical rodent models

Design and Synthesis of 4‑Heteroaryl 1,2,3,4-Tetrahydroisoquinolines as Triple Reuptake Inhibitors

A series of 4-bicyclic heteroaryl 1,2,3,4-tetrahydroisoquinoline inhibitors of the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT) was discovered. The synthesis and structure–activity relationship (SAR) of these triple reuptake inhibitors (TRIs) will be discussed. Compound <b>10i</b> (AMR-2), a very potent inhibitor of SERT, NET, and DAT, showed efficacy in the rat forced-swim and mouse tail suspension models with minimum effective doses of 0.3 and 1 mg/kg (<i>po</i>), respectively. At efficacious doses in these assays, <b>10i</b> exhibited substantial occupancy levels at the three transporters in both rat and mouse brain. The study of the metabolism of <b>10i</b> revealed the formation of a significant active metabolite, compound <b>13</b>