Positive allosteric modulators (PAMs)
of the M4 muscarinic
acetylcholine receptor (mAChR) represent a novel approach for the
treatment of psychotic symptoms associated with schizophrenia and
other neuropsychiatric disorders. We recently reported that the selective
M4 PAM VU0152100 produced an antipsychotic drug-like profile
in rodents after amphetamine challenge. Previous studies suggest that
enhanced cholinergic activity may also improve cognitive function
and reverse deficits observed with reduced signaling through the N-methyl-d-aspartate subtype of the glutamate receptor
(NMDAR) in the central nervous system. Prior to this study, the M1 mAChR subtype was viewed as the primary candidate for these
actions relative to the other mAChR subtypes. Here we describe the
discovery of a novel M4 PAM, VU0467154, with enhanced in vitro potency and improved pharmacokinetic properties
relative to other M4 PAMs, enabling a more extensive characterization
of M4 actions in rodent models. We used VU0467154 to test
the hypothesis that selective potentiation of M4 receptor
signaling could ameliorate the behavioral, cognitive, and neurochemical
impairments induced by the noncompetitive NMDAR antagonist MK-801.
VU0467154 produced a robust dose-dependent reversal of MK-801-induced
hyperlocomotion and deficits in preclinical models of associative
learning and memory functions, including the touchscreen pairwise
visual discrimination task in wild-type mice, but failed to reverse
these stimulant-induced deficits in M4 KO mice. VU0467154
also enhanced the acquisition of both contextual and cue-mediated
fear conditioning when administered alone in wild-type mice. These
novel findings suggest that M4 PAMs may provide a strategy
for addressing the more complex affective and cognitive disruptions
associated with schizophrenia and other neuropsychiatric disorders.
Schizophrenia patients exhibit deficits in signaling of the M 1 subtype of muscarinic acetylcholine receptor (mAChR) in the prefrontal cortex (PFC) and also display impaired cortical long-term depression (LTD). We report that selective activation of the M 1 mAChR subtype induces LTD in PFC and that this response is completely lost after repeated administration of phencyclidine (PCP), a mouse model of schizophrenia. Furthermore, discovery of a novel, systemically active M 1 positive allosteric modulator (PAM), VU0453595, allowed us to evaluate the impact of selective potentiation of M 1 on induction of LTD and behavioral deficits in PCP-treated mice. Interestingly, VU0453595 fully restored impaired LTD as well as deficits in cognitive function and social interaction in these mice. These results provide critical new insights into synaptic changes that may contribute to behavioral deficits in this mouse model and support a role for selective M 1 PAMs as a novel approach for the treatment of schizophrenia.
Herein, we report the structure-activity relationships within a series of potent, selective, and orally bioavailable muscarinic acetylcholine receptor 4 (M) positive allosteric modulators (PAMs). Compound (VU0467485) possesses robust M PAM potency across species and efficacy in preclinical models of schizophrenia. Coupled with an attractive DMPK profile and suitable predicted human PK, (VU0467485) was evaluated as a preclinical development candidate.
A functional
high throughput screen identified a novel chemotype
for the positive allosteric modulation (PAM) of the muscarinic acetylcholine
receptor (mAChR) subtype 5 (M5). Application of rapid analog,
iterative parallel synthesis efficiently optimized M5 potency
to arrive at the most potent M5 PAMs prepared to date and
provided tool compound 8n (ML380) demonstrating modest
CNS penetration (human M5 EC50 = 190 nM, rat
M5 EC50 = 610 nM, brain to plasma ratio (Kp) of 0.36).
This letter describes the chemical optimization of a novel series of M4 positive allosteric modulators (PAMs) based on a 5-amino-thieno[2,3-c]pyridazine core, developed via iterative parallel synthesis, and culminating in the highly utilized rodent in vivo tool compound, VU0467154 (5). This is the first report of the optimization campaign (SAR and DMPK profiling) that led to the discovery of VU0467154, and details all of the challenges faced in allosteric modulator programs (steep SAR, species differences in PAM pharmacology and subtle structural changes affecting CNS penetration).
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