spec sheet8 rows
T440 A Takeda M1 positive allosteric modulator aimed at constipation rather than cognition; it amplifies the enteric nervous system's own acetylcholine signaling to produce coordinated, propagating colonic contractions.
- Produces propagating, coordinated colonic contractions rather than raised tone
- Maximum defecation effect in rats about twice that of prucalopride
- Orally active, with bioavailability of 40 percent in rats and 31 percent in dogs
- No loss of effect across five days of repeated dosing
- No activity at M2 through M5 up to 10 micromolar
- Looser, wetter stool, the expected cost of a cholinergic prokinetic
- No cooperativity value published, so its gut and brain margin cannot be compared with the cognition compounds
- No cardiovascular, seizure or chronic toxicity screening reported
- No human data of any kind
Overview
The most useful compound in this group for understanding the others. Every cognition program in the M1 PAM field spent years engineering the bowel effect out; a constipation program takes the same receptor, the same class and the same mechanism and treats that effect as the product. Reading T440 next to T-495 makes it obvious that a side effect and an indication can be one pharmacology at two doses.
- At the dose where each drug worked best in anesthetized rats, one T440-driven contraction pushed 233 microliters of colonic content; prucalopride managed 22 and neostigmine 25. The three drugs produced similar numbers of contractions, so what differed was coordination, not force.
- Five days of repeated dosing produced no loss of effect on defecation, which is not the usual behavior of a drug that works through cholinergic transmission.
Mechanism
M1 receptors sit on neurons of the myenteric and submucosal plexuses and on the epithelium in the human colon, and the same localization holds in mouse, rat, dog and pig [1]. T440 potentiates at M1 with an EC50 of 6.3 nM at the human receptor, 5.9 nM at rat and 5.1 nM at dog; its own activity at M1 is above 10,000 nM in every species, and it shows neither modulation nor agonism at M2 through M5 up to 10,000 nM [1]. Because it amplifies rather than initiates, the contractions follow the enteric circuitry's own sequencing: oral dosing at 0.03 mg/kg in conscious dogs produced high amplitude contractions that propagated from the ileum to the distal colon and lined up in time with defecation episodes [1].
Coordination, not contraction count, is what separates it from the alternatives; at each drug's most effective dose in anesthetized rats, T440 moved 233 microliters of content per contraction against 22 for prucalopride and 25 for neostigmine [1]. The paper reports T440's potency and subtype selectivity but not a cooperativity value, so where it falls on the alpha scale that distinguishes the cognition compounds is not established in the published record.
receptor fingerprint
M1 (CHRM1)Positive Allosteric Modulator
M2 through M5 (CHRM2 to CHRM5)No modulation and no agonism
M1 (CHRM1), direct activationWeak Agonist
Safetyrisks and cautions, not medical advice
T440 has not been given to humans and no clinical safety data exist. In conscious rats, doses up to 30 mg/kg produced no signs of aversion, stress or discomfort, and in conscious dogs the same held up to 0.3 mg/kg [1]. Fecal scores, a measure of stool moisture, rose with T440 and with neostigmine but not with prucalopride, which is the expected cost of a cholinergic prokinetic and is the same readout that counts as a side effect in the cognition programs [1].
The comparison that matters most for safety is neostigmine, which enhanced defecation about as effectively but caused uncoordinated skeletal muscle contraction at 0.3 mg/kg and was lethal at 1 mg/kg; T440 reached its effect at doses far below anything that produced behavioral signs [1]. The published work covers behavioral observation across five days of repeated dosing and does not report cardiovascular, seizure or chronic toxicity screening, so those questions stay open.
History
Synthesized at Takeda Pharmaceutical Company and studied by Takeda's Gastroenterology Drug Discovery Unit together with John Furness's group at the Florey Institute in Melbourne and collaborators in Adelaide; the work appeared in 2020 [1]. It sits in the same Takeda M1 PAM effort that produced the cognition molecules but points the other way. Sibling modulators from that program, T662 and T523, reversed opioid-induced constipation and the constipation of aging in mice, and stimulated colorectal emptying in dog, mouse and rat [2].
Reputation
Barely known outside neurogastroenterology, and worth knowing mostly for the inversion it represents. The name is also a trap: a completely different compound called T-440 is a phosphodiesterase 4 inhibitor studied in isolated human bronchus in the 1990s, and a search on the bare code will mix the two. The muscarinic compound is written T440 in its own literature.
Subjective profileweighing the evidence above
The most useful compound in this group for understanding the others. Every cognition program in the M1 PAM field spent years engineering the bowel effect out; a constipation program takes the same receptor, the same class and the same mechanism and treats that effect as the product. Reading T440 next to T-495 makes it obvious that a side effect and an indication can be one pharmacology at two doses.
Resources
This entry is here for reference.
Research
- 1.Effects and sites of action of a M1 receptor positive allosteric modulator on colonic motility in rats and dogs compared with 5-HT4 agonism and cholinesterase inhibition
- 2.Muscarinic receptor 1 allosteric modulators stimulate colorectal emptying in dog, mouse and rat and resolve constipation
2 listed here; entry last updated August 2026
Reviews
My notesprivate to this device
FAQ
Is this related to the M1 drugs being developed for Alzheimer's?
Same receptor, same class, opposite goal. The cognition programs spent years designing the bowel effect out. A constipation program takes it as the endpoint and does not need the compound to reach the brain at all.
How does it differ from prucalopride?
Prucalopride acts at 5-HT4 receptors and raises the number of contractions more than their pushing power. T440 amplifies the enteric nervous system's own acetylcholine signaling at M1, so contractions arrive in the sequence the gut would have used anyway; in the rat measurements it moved roughly ten times more content per contraction.
Why not just use a cholinesterase inhibitor for constipation?
Neostigmine works, but in the same rat study it caused uncoordinated skeletal muscle contraction at 0.3 mg/kg and was lethal at 1 mg/kg. Raising acetylcholine everywhere leaves almost no gap between the useful dose and the dangerous one, which is the gap a subtype-selective modulator is meant to open.
Has it been tested in people?
The published record on T440 covers rats, dogs and tissue from five species, and that is where it ends.
Adverse effects
- Looser, wetter stool, the expected cost of a cholinergic prokinetic
- No cooperativity value published, so its gut and brain margin cannot be compared with the cognition compounds
- No cardiovascular, seizure or chronic toxicity screening reported
- No human data of any kind