data + articles · 2 listed
newest 2017spec sheet7 rows
PT-1284 A Pfizer M1 positive allosteric modulator whose tritiated form became the first radioligand for the M1 allosteric site, letting a program rank modulators by how tightly they bind instead of only by what they do.
- First radioligand for the M1 allosteric site
- Measures M1 PAM binding affinity directly rather than inferring it
- Binding affinity tracks functional potency across nineteen modulators
- Separates the modulator site from the site used by allosteric agonists
- Potentiates carbachol in native hippocampal tissue, not only in cell lines
- A reagent rather than a candidate; never dosed in humans
- In vivo tolerability was not characterized
- Requires acetylcholine present to bind well, so it cannot label the unoccupied receptor
- Binding affinity turned out not to predict tolerability for this class
Overview
A reagent, not a candidate, and the most quietly consequential compound in this group. Before it, every muscarinic radioligand labeled the orthosteric site, so nobody could measure a modulator's affinity directly. It also settled a question by accident: binding and function track each other almost perfectly across M1 PAMs, which means the tolerability failures in this class were never an assay problem.
- The radioligand only binds well when acetylcholine is already sitting in the orthosteric site, which is cooperativity running in the other direction; the neurotransmitter raises the modulator's affinity just as the modulator raises the neurotransmitter's.
- M1 allosteric agonists barely displace it, needing more than 30 micromolar, which says an allosteric agonist and a positive allosteric modulator are not necessarily occupying the same pocket on the receptor.
Mechanism
PT-1284 potentiated at M1 in a fluorometric imaging plate reader assay with an EC50 of 36 nM, and potentiated carbachol in hippocampal slice electrophysiology with an EC50 of 165 nM [1]. Its cooperativity appears as a measured shift rather than a fitted constant: at 10 micromolar it left-shifted the Ki for displacing [3H]N-methylscopolamine roughly 19-fold [1]. The same relationship read backwards is what made it useful as a reagent.
Tritiated PT-1284 bound human M1 with a Kd of 4.23 nM and a Bmax of 6.38 pmol per milligram of protein in the presence of 1 mM , because the modulator's own affinity for the site depends on the orthosteric site being occupied [1]. Selective M1 PAMs displaced it in a concentration-dependent way, while M1 and orthosteric agonists bound weakly, above 30 micromolar, which places the modulator site apart from the one those agonists use [1]. Across nineteen M1 PAMs, affinity in the [3H]PT-1284 assay correlated with functional potency at an R squared of 0.86 [1].
receptor fingerprint
M1 (CHRM1)Positive Allosteric Modulator
M1 (CHRM1), hippocampal slicePositive Allosteric Modulator
M1 (CHRM1) site, as [3H]PT-1284Radioligand
Safetyrisks and cautions, not medical advice
PT-1284 is a laboratory reagent rather than a therapeutic candidate, and no in vivo tolerability data for it have been published; the paper characterizing it covers receptor binding, cell assays and hippocampal slice electrophysiology only [1]. The tritiated form carries the ordinary handling requirements of a beta-emitting radioligand and is used on membranes and tissue sections.
Class risk is worth stating even though it was never measured for this molecule: the same Pfizer group reported the following year that PF-06827443, an M1 PAM designed to have minimal agonist activity, still caused cholinergic adverse events and convulsion in rats and dogs at therapeutic indices no better than compounds with more agonist activity [2]. That finding is about PF-06827443 and not about PT-1284, but it is why binding affinity at the M1 allosteric site stopped being treated as a sufficient predictor of a tolerable compound.
History
Reported in 2016 by Deborah Smith and colleagues across Pfizer's neuroscience and pain research unit and worldwide medicinal chemistry groups in Cambridge, Massachusetts and Groton, Connecticut [1]. It arrived at a moment when the field had many M1 PAMs and no direct way to measure their binding, because every available muscarinic radioligand labeled the orthosteric site. Pfizer reported the following year that its M1 PAM PF-06827443 produced convulsion and cholinergic adverse events in rats and dogs [2].
Reputation
Known only to people who run muscarinic binding assays; it is discussed as a reagent, never as a drug. Its lasting contribution is methodological. With a correlation of 0.86 between binding affinity and functional potency across nineteen modulators, it established that the two readouts measure the same thing, so a discovery program could screen on binding and trust the ranking.
Subjective profileweighing the evidence above
A reagent, not a candidate, and the most quietly consequential compound in this group. Before it, every muscarinic radioligand labeled the orthosteric site, so nobody could measure a modulator's affinity directly. It also settled a question by accident: binding and function track each other almost perfectly across M1 PAMs, which means the tolerability failures in this class were never an assay problem.
Resources
This entry is here for reference.
Research
- 1.Characterization of a Novel M1 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator Radioligand, [3H]PT-1284
- 2.Design and Synthesis of γ- and δ-Lactam M1 Positive Allosteric Modulators (PAMs): Convulsion and Cholinergic Toxicity of an M1-Selective PAM with Weak Agonist Activity
2 listed here; entry last updated July 2026
Reviews
My notesprivate to this device
FAQ
Is PT-1284 a drug?
No. It is a tool compound, and the version that gets used is the tritium-labeled form, a reagent for measuring how tightly other M1 modulators bind to the allosteric site.
Why does the assay need acetylcholine in the buffer?
Because the allosteric site only becomes high affinity once the orthosteric site is occupied. Cooperativity works both ways, so the binding assay is run with 1 mM acetylcholine present and the reported Kd of 4.23 nM belongs to that condition.
Does tight binding mean a modulator will be safe?
No, and that is one of the more useful things this literature settled. Affinity in the PT-1284 assay predicts functional potency almost perfectly, yet a Pfizer modulator built with minimal agonist activity still produced convulsion in rats and dogs. Potency and tolerability come apart somewhere other than the binding step, which is where the cooperativity work picked up the question.
How is this different from a PET tracer?
A tritium-labeled ligand is for benchtop work on membranes and tissue sections. Tritium is a weak beta emitter and cannot be imaged through a living body, so this reagent measures affinity in vitro; it is not a scanning agent.
Adverse effects
- A reagent rather than a candidate; never dosed in humans
- In vivo tolerability was not characterized
- Requires acetylcholine present to bind well, so it cannot label the unoccupied receptor
- Binding affinity turned out not to predict tolerability for this class