Douglas Yao (@DouglasYaoDY): "This vial contains a new drug called PAC-832, which I recently invented to treat Alzheimer’s disease. It is the world’s first selective GalR1 antagonist.
I designed and synthesized PAC-832 in a chemistry lab I built in my garage. (1/16)" | XCancel
Douglas Yao
@DouglasYaoDY
22h
This vial contains a new drug called PAC-832, which I recently invented to treat Alzheimer’s disease. It is the world’s first selective GalR1 antagonist.
I designed and synthesized PAC-832 in a chemistry lab I built in my garage. (1/16)
Jun 27, 2026 · 4:19 PM UTC
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Douglas Yao
@DouglasYaoDY
22h
PAC-832 is the first drug of its kind. It works by selectively blocking a receptor in the brain called “galanin receptor 1,” or GalR1. The drug has sub-micromolar potency for GalR1 and >30x selectivity over GalR2/3. (2/16)
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Douglas Yao
@DouglasYaoDY
22h
When administered to mice, PAC-832 significantly improves their memory across multiple different memory tests. (3/16)
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Douglas Yao
@DouglasYaoDY
22h
PAC-832 also has excellent manufacturability and chemical properties (stability, solubility, etc.), low toxicity, and great pharmacokinetics, including being readily absorbed through the stomach and passing the blood-brain barrier - all less appreciated, but no less critical properties needed for an oral neurological drug to succeed (4/16).
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Douglas Yao
@DouglasYaoDY
22h
PAC-832 is currently undergoing IND-enabling studies and will be the first galanin-targeting drug in 15 years (and first selective GalR1-targeting drug ever) to enter clinical trials. Read more about this drug here: pacepharmaceuticals.com/ (5/16)
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Douglas Yao
@DouglasYaoDY
21h
What’s GalR1, and what does it have to do with AD?
GalR1 is one of three receptors for a molecule called “galanin,” which acts as a signaling molecule in mammalian brains. Galanin isn’t nearly as well-characterized as other neurotransmitters like dopamine or serotonin, yet it’s been shown to regulate many of our key bodily functions, like pain, metabolism, mood, sleep, and memory. (6/16)
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Douglas Yao
@DouglasYaoDY
21h
In the 1980s, abnormal galanin signaling was tied to Alzheimer’s through several clinical and scientific observations: (1) brains from deceased AD patients contained many more galanin-producing neurons than normal, concentrated in the basal forebrain - a key memory region in the brain, (2) galanin prevented acetylcholine (ACh), a neurotransmitter essential for memory, from being released when applied to brain slices from rodents/monkeys, and (3) galanin treatment impaired memory in live rodents. (7/16)
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Douglas Yao
@DouglasYaoDY
21h
These observations led scientists in the 90s to hypothesize that a drug that blocked the action of galanin in the brain could increase ACh levels and improve memory, similar to how acetylcholinesterase inhibitors like the AD drug donepezil work.
An initial cohort of peptide galanin antagonists was developed. These drugs were unable to pass the blood-brain barrier due to their size and thus had to be administered by direct injection into the brain - feasible for a mouse, obviously not feasible for a human. Still, their effects served as an important proof of concept: a galanin inhibitor could improve memory (in rodents at least), so long as it reached the brain. (8/16)
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Douglas Yao
@DouglasYaoDY
21h
The first small molecule inhibitors of galanin with potential to pass the blood-brain barrier appeared in the early 2000s. A few high-throughput screens were carried out for GalR1 (galanin receptor 1) antagonism by big pharma companies Schering-Plough (now part of Merck) and J&J, producing two promising lead compounds/series. However, none of them were developed further due to various practical issues - difficulty of synthesis in the former case, reactivity and solubility issues in the latter case. (9/16)
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Douglas Yao
@DouglasYaoDY
21h
Later in the 2000s, a more complete picture of galanin signaling emerged. New studies showed that galanin surprisingly protected neuronal health in various contexts, suggesting that neurons in AD patients overexpressed galanin to ‘protect’ the neurons from neurotoxic factors brought on by AD progression. There were now two conflicting mechanisms tied to galanin signaling - one of ACh inhibition, leading to cognitive impairment, and one of neuronal protection.
The newfound pleiotropic nature of galanin threw cold water on the galanin therapeutic hypothesis - it suggested that a blanket inhibitor of galanin ran the risk of causing harm by blocking galanin’s protective effects. (10/16)
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Douglas Yao
@DouglasYaoDY
21h
However, the seemingly contradictory harmful vs. protective effects of galanin were soon resolved by molecular research tied to the three galanin receptors, known as GalR1-3. The galanin receptors are part of a large...