spec sheet9 rows
WAY-100635 is the molecule that a very large part of what is known about the serotonin 5-HT1A receptor was measured with. Wyeth described it across 1995 and 1996 as the first potent, selective and silent antagonist at that receptor: it displaced tritiated 8-OH-DPAT from rat hippocampal 5-HT1A sites with an IC50 near 1.35 nM, blocked every classical 5-HT1A agonist response tested, and produced none of those responses itself [2][3]. That combination is rarer than it sounds, and it made the compound a fixture; well over a thousand published papers now use it, nearly always in the same design, where an effect is produced with a serotonin agonist and then removed with WAY-100635 to show which receptor carried it. Labelled with carbon-11 on the cyclohexanecarbonyl group it also became the standard positron emission tomography tracer for mapping 5-HT1A receptors in living human brain [17][29]. The reputation for cleanliness was later challenged. A 2006 screen reported low nanomolar binding and full agonist activity at dopamine D4 receptors and said outright that conclusions resting on WAY-100635 as a selective 5-HT1A antagonist may need re-examining [9]; a second laboratory measured the same receptor and reached almost the opposite conclusion [10]. That argument is not settled. WAY-100635 has never been given to anyone as a medicine, and the only human exposure on record is a microgram tracer dose in a brain scan.
- Nothing here is a benefit to a person. WAY-100635 is a laboratory reagent with no human therapeutic use, no approved indication anywhere, and no dose that anyone should take
- As a research tool it does one job unusually well: at roughly 0.03 mg/kg in the rat it removes a 5-HT1A agonist's effect while producing none of its own, which is what allows an effect to be assigned to that receptor
- Labelled with carbon-11 it is the standard positron emission tomography tracer for mapping 5-HT1A receptors in living human brain, and most of what is known about that receptor in people was measured with it
- Tritiated WAY-100635 was the first antagonist radioligand for the 5-HT1A receptor, and it labels a receptor population 50 to 60 percent larger than the agonist ligand it replaced
- It is the tool that showed pindolol occupies human 5-HT1A receptors at clinical doses, which is the direct test of a long-running idea about speeding up antidepressant response
- No human adverse-event profile exists at any pharmacologically active dose, because no pharmacologically active dose has ever been given to a person
- Dopamine D4 receptor activation, strong enough at higher doses for rats to recognise it as a distinct drug state that selective D4 antagonists abolish
- A brain-penetrant metabolite, WAY-100634, formed by cleavage of the amide bond, carrying its own activity at 5-HT1A receptors, alpha-1 adrenoceptors and dopamine D4
- Affinity at alpha-1 adrenoceptors, with subtype-resolved values as low as a few nanomolar at alpha-1D, close enough to the primary target to matter
- Effects that reverse direction depending on where the compound is put; infused into the median raphe it was anxiolytic in mice, the opposite of what autoreceptor blockade there predicts
- As a radiotracer the exposure of note is radiation rather than pharmacology, and the human absorbed dose turned out to be far higher than the rodent estimate had suggested, with the urinary bladder wall as the critical organ
Mechanism
The defining action is competitive antagonism at the receptor, at both of the places that receptor sits. On raphe serotonin neurons it blocks the somatodendritic autoreceptor that normally shuts those cells down, and on hippocampal CA1 pyramidal cells it blocks the postsynaptic receptor. The original characterisation showed dose-dependent blockade at both sites with no action of its own, and in living animals it reversed the whole classical 5-HT1A agonist set: suppression of dorsal raphe firing, the serotonin behavioural syndrome, hypothermia, hyperphagia and the rise in plasma ACTH [3].
The word doing the most work in the original description is silent. Several earlier compounds called antagonists, including the closely related Wyeth compound WAY-100135, turned out to be partial agonists, which contaminates every experiment they appear in. The first pharmacological profile found no evidence of or partial agonist activity in any functional assay [2], and tested head to head by microdialysis, WAY-100635 given alone did not move hippocampal at all while (S)-WAY-100135 given alone lowered it; WAY-100635 reversed the 8-OH-DPAT with an ED50 near 0.03 mg/kg in the rat, so the useful dose range is very low [8]. That low working dose matters later.
Silence has since been qualified twice, in opposite directions, and both results stand. In cloned human receptors expressed at high density in HeLa cells, lowering sodium exposes constitutive receptor activity, and under those conditions WAY-100635 suppresses it: that is inverse agonism, not neutrality, although it is weaker than spiperone's, and it was blocked by (S)-WAY-100135 and abolished by pertussis toxin, so it is genuinely receptor-mediated [5]. In native rat hippocampal membranes, which also show constitutive activity, the same measurement puts WAY-100635 on the other side of the line: it produced no inverse agonism of its own and instead blocked the inverse agonism of spiperone and methiothepin, which is the behaviour of a neutral [6]. The difference tracks the system rather than the molecule, and the practical reading is that silent is accurate in native tissue and an overstatement in a high-expression recombinant line.
Affinity at the primary target is not in dispute. Independent depositions in ChEMBL put the human Ki between roughly 0.16 and 2.2 nM, with rat Kd values near 0.1 to 0.2 nM, and the recombinant human receptor gives a Kd of 0.32 nM for the tritiated compound itself [4]. The original selectivity screen ran the molecule against other subtypes and against major neurotransmitter receptor, reuptake and ion channel sites, and found more than a hundredfold selectivity across that panel [2]; the transporter is essentially untouched, at a Ki above 1000 nM.
What is in dispute is D4. A screen run through the NIMH Psychoactive Drug Screening Program found 16 nM binding at D4.2, and follow-up work put the dissociation constant of tritiated WAY-100635 at D4.2 at 2.4 nM, only about tenfold weaker than its value, with a binding Ki of 3.3 nM at D4.4. In cells expressing D4.4 the compound behaved as a full with an EC50 near 9.7 nM, and its major WAY-100634 was a nearly full agonist an order of magnitude more potent still, at 0.65 nM [9]. A year later a different group repeated the measurement and got a different answer: pKi 7.42 at the human D4.4 receptor against 9.51 at , a functional pEC50 of 6.63, and a maximum response of only 19 percent of 's, which is a weak partial rather than a full one, plus an potency two and a half log units apart between the two receptors [10]. Two competent laboratories, the same receptor, incompatible numbers.
Behaviour tips the argument partly back toward the alarm. Rats can be trained to recognise WAY-100635 as a drug cue, and that cue is completely blocked by the selective D4 antagonists sonepiprazole and A-381393, is not touched by agonists, and is not produced by pindolol [11]. Dose is the hinge. Rats trained at 10 micromol per kg learned the discrimination; rats trained at 0.74 micromol per kg never learned it across more than three months of sessions. WAY-100635 also substitutes fully for the late phase of an LSD cue, an effect the same group assigns to D4 [12], and in amphetamine-trained rats the authors read the low doses as blockade and the high doses as D4 stimulation [13]. The practical reading is that the D4 effect is real in a living animal but sits an order of magnitude or more above the dose needed to block , so it threatens high-dose and locally infused experiments far more than ordinary low systemic ones.
Two further off-targets belong in the same paragraph. The amide bond is cleaved in the body to WAY-100634, the descyclohexanecarbonyl fragment, which crosses into brain and is described as having high affinity for both receptors and alpha-1 adrenoceptors [15]. Alpha-1 affinity for the parent was called moderate in the 1996 microdialysis work, where WAY-100635 did not reverse prazosin [8]; subtype-resolved depositions in ChEMBL are less reassuring, putting alpha-1D at a Ki near 4.6 nM and alpha-1A near 19 nM, which is a much narrower window over than the original headline of more than a hundredfold selectivity suggests.
receptor fingerprint
receptor (postsynaptic)Competitive antagonist, neutral at native receptors and weakly inverse-agonist in a high-expression recombinant line; the defining and primary action
Somatodendritic autoreceptor (dorsal and median raphe)Blocks the autoreceptor that normally suppresses raphe serotonin neuron firing
D4 receptorAgonist. Whether it is a potent full agonist or a weak partial one is genuinely disputed between laboratories
Alpha-1 adrenoceptorsBinds; called moderate affinity in the original work, but tighter than that in subtype-resolved data
transporterEssentially inactive; reported here as a negative result rather than an effect
and D3 receptorsWeak binding only; not a functional target at ordinary concentrations
Evidencehow good the literature is
The literature is enormous and almost entirely instrumental. More than 1,800 records in PubMed mention WAY-100635, and the overwhelming majority use it as a reagent rather than study it: an effect is produced, WAY-100635 is given, and the effect either survives or does not. Very little of that work is about the compound.
The primary characterisation is strong for its era. The 1996 Wyeth paper reports binding, autoradiography, in vitro and in vivo electrophysiology, neuroendocrine challenge and behaviour in one place, and establishes tritiated WAY-100635 as the first antagonist radioligand for the 5-HT1A receptor, with a Bmax consistently 50 to 60 percent higher than the agonist ligand, which is what an antagonist should do at a G-protein-coupled receptor [3]. The silence claim was tested directly against a partial-agonist comparator and held [8], and it has since been probed harder, with the answer coming out different in a recombinant cell line than in native tissue [5][6]. That is a qualification rather than a refutation, and it is the kind of qualification a twenty-year-old tool compound should be expected to accumulate.
The selectivity claim is where the evidence is genuinely contested. Chemel and colleagues report full D4 agonism at low nanomolar concentrations and conclude that studies using the compound as a selective 5-HT1A antagonist may need re-evaluation [9]. Martel and colleagues, using functional GTP-gamma-S assays and antagonist potency measurements, report high selectivity for 5-HT1A over D4 and a maximum D4 response of only 19 percent [10]. Neither has been retracted and neither has clearly won. A third line of behavioural work supports a real D4 action at higher doses [11][12][13], which is the most defensible synthesis available: the D4 activity exists, its potency is disputed, and dose decides whether it matters.
The human evidence is imaging evidence, and it is substantial. The carbon-11 tracer delineates the receptor with unusual clarity, reaching a medial temporal cortex to cerebellum ratio near 25 in the first human study [17], the kinetic modelling was worked out in volunteers [18], and the first real application was drug occupancy: pindolol and penbutolol were shown to occupy human 5-HT1A receptors at clinical doses while tertatolol did not [19]. Reviews of the field name it the most successful ligand for the target [29][30], and it has produced findings in social anxiety disorder, where amygdala binding was about 21 percent lower in unmedicated patients [26], and in temporal lobe epilepsy, where limbic binding was reduced on the epileptogenic side even in patients whose structural imaging and glucose metabolism looked normal [27].
Depression is where the same tracer produced a genuine, still open contradiction, and it is the best available lesson in how much a tool's imperfections can cost. Of eight studies asking whether 5-HT1A binding is altered in major depression, four found it decreased, two found no change and two found it increased, and a review by the group with the least stake in either answer concluded the results do not reliably answer the question and cannot be pooled [22]. One paper shows why in a way that is hard to argue with: in a single dataset, binding was higher in unmedicated depressed patients on one outcome measure, no different on another, and lower on a third, with the answer turning on whether cerebellar grey or cerebellar white matter was used as the reference region [23]. The cerebellum was assumed to be free of 5-HT1A receptors and it is not, and the residual signal there is partly the same brain-penetrant metabolite problem the carbon-11 label was moved to solve. Both camps published careful work; the disagreement is methodological rather than careless [24][25].
One animal example shows why the receptor caveats are not academic either. Infusing WAY-100635 directly into the median raphe of mice increased open-arm exploration and reduced risk assessment on the elevated plus-maze, which is an anxiolytic pattern, when blocking somatodendritic autoreceptors there predicts the opposite; the dorsal raphe gave nothing, and reduced movement did not explain it [14]. The authors proposed a projection to the periaqueductal gray. That reading may well be right, and the original Wyeth work had already found anxiolytic-like effects for the compound in the mouse light and dark box [3]. It is also true that 3.0 micrograms delivered into 0.1 microlitres of tissue is a local concentration far outside any selectivity window measured in a test tube, which is exactly the situation in which a second receptor stops being hypothetical.
Dosingtypical ranges, not medical advice
interested in protocols and clinical dosages? make an account to see them! ^_^
Safetyrisks and cautions, not medical advice
There is no human safety profile for WAY-100635 in the sense that phrase usually carries, because no one has ever been given it as a medicine. It was never approved anywhere, and no therapeutic dose exists to describe. A search of the trials registry finds it in five studies and it is the camera in every one of them, never the drug; the closest thing to a clinical record is a completed Phase 1 study in thirteen healthy men that used [11C]WAY-100635 to measure how much 5-HT1A receptor a different compound occupied.
Humans have been exposed to it, and the route is worth being precise about. As [carbonyl-11C]WAY-100635 it has been injected into volunteers and patients for positron emission tomography since 1996 [17][18], and the technique remains in use [28]. The injected mass is on the order of 1.5 to 3.0 micrograms per scan [21], which is a tracer quantity rather than a pharmacological one. The molecule does occupy its receptor at that mass, because occupying the receptor is the whole point, but it occupies a small fraction of it and no pharmacological or physiological effect has been reported after any such injection. That is real human exposure and it is why any human tolerability experience exists at all, but it is not evidence that a pharmacologically active dose would be tolerated, and it should not be read that way.
The measurable human risk of the procedure is radiation, not pharmacology, and on that count this tracer is a notable outlier. A dedicated dosimetry study in six volunteers found the urinary bladder wall to be the critical organ at about 0.19 mGy per MBq, and found the human absorbed doses to be roughly 6.6 times the rat estimate for kidney and 60.6 times the rat estimate for bladder wall, meaning the rodent extrapolation used through the preceding decade of scanning had understated the exposure badly [20]. The practical consequence is stated in the same paper: under United States Radioactive Drug Research Committee rules a single dose may not exceed 300 MBq in a man or 227 MBq in a woman, with at most three such injections a year.
No adverse event has ever been reported for this compound in a person. That is not the same as being shown to be safe: imaging methods papers routinely carry no tolerability section at all, so the absence of reports is weak evidence rather than a clean bill.
What is known at pharmacologically active doses comes from animals, and two facts there are load-bearing for anyone tempted to treat this as a clean serotonin blocker. It activates dopamine D4 receptors, strongly enough at higher doses for a rat to recognise the drug state [11]. And its metabolite WAY-100634 is brain-penetrant and carries its own receptor activity [15][9], so the parent is not the only thing acting. No oral human pharmacokinetics, no toxicology package and no repeated-exposure data are in the public record. It is sold for laboratory work only.
History
WAY-100635 came out of Wyeth's 5-HT1A programme, based at the company's Maidenhead laboratories in the United Kingdom, with the binding work later extended at Wyeth-Ayerst in Princeton [4]. Its immediate ancestor was WAY-100135, and the problem the programme set out to solve was that the field had no clean tool: the available compounds were agonists, partial agonists, or antagonists that were not selective, and several molecules called antagonists turned out on closer inspection to have intrinsic activity. The team coined the term silent antagonist for what they were after, in a 1993 review whose title says plainly that they wanted both things at once, research tools and therapeutic agents [1].
It is worth being clear that this was a drug programme before it was a tool programme. The molecule was first disclosed in a Wyeth patent application, European publication EP 0512755 A2, filed with a priority date of 2 May 1991 by John Wyeth and Brother Ltd, inventors Ian Cliffe and Howard Mansell, where it appears as Example 3 with a 5-HT1A binding IC50 of 2.2 nM. That document claims the series for treating anxiety and lists antidepressant, antihypertensive, sleep and wake, feeding and sexual function uses alongside it. By the time the first pharmacological profile was published in 1995 the framing had shifted, and that paper ends by saying the compound will be used as a standard antagonist in further studies of 5-HT1A receptor function rather than as a candidate for anything [2]. That is where it stayed. The comprehensive characterisation followed in 1996, with eighteen authors spanning Wyeth and academic groups in France and Italy [3], and the chemist who invented it wrote the retrospective account of how it became a radioligand [7].
Adoption was immediate and it went in two directions. In pharmacology the compound became the default way to prove an effect was 5-HT1A mediated. In imaging it became a radioligand, and the story of how is worth knowing because it is a rare case of a labelling decision being visibly load-bearing. The first attempt put carbon-11 on the methoxy group, and that version failed: the amide bond is cleaved in the body to WAY-100634, which is brain-penetrant and itself binds 5-HT1A receptors and alpha-1 adrenoceptors, so the labelled fragment followed the parent into the brain and contaminated the signal. At sixty minutes after injection only 5 percent of the radioactivity in human plasma was still the parent compound [15]. Moving the label to the cyclohexanecarbonyl group put the carbon-11 on the piece that leaves rather than the piece that stays. That was then confirmed rather than assumed: the main labelled metabolite of the new version was identified as cyclohexanecarboxylic acid, and injecting that acid into a monkey on its own showed only low brain uptake, with signal contrast roughly three times better in monkey and ten times better in human [16]. Human imaging with [carbonyl-11C]WAY-100635 began in 1996 [17] and the quantification methods followed [18].
The revision came a decade later. In 2006 a screen through the NIMH Psychoactive Drug Screening Program flagged dopamine D4 binding, and the follow-up characterisation reported full agonist activity along with a warning that a great deal of published work might need re-reading [9]. A rebuttal followed within a year arguing the selectivity was fine [10], and a separate behavioural line then showed that rats treat higher doses of the compound as a D4 agonist [11]. None of this removed WAY-100635 from use. It never became a medicine and was never taken past preclinical development as one; it remains the reference 5-HT1A antagonist and the reference positron emission tomography ligand for the receptor. What changed is that it can no longer be called clean without a qualifier.
Subjective profileweighing the evidence above
A laboratory reagent, not a substance to take. Nothing here is a benefit to a person. The reason it is worth reading about is that an enormous slice of the published 5-HT1A literature was produced with this one molecule, so whatever is wrong with the molecule is also wrong with that literature, and there is a real unresolved argument about how selective it actually is.
Resources
This entry is here for reference.
Research
- 1993first citedSilent 5-HT1A receptor antagonists: utility as research tools and therapeutic agents
- 1996most active year4 papers
- 2013most recentHigher in vivo serotonin-1a binding in posttraumatic stress disorder: a PET study with [11C]WAY…
- 1.Silent 5-HT1A receptor antagonists: utility as research tools and therapeutic agents
- 2.A pharmacological profile of the selective silent 5-HT1A receptor antagonist, WAY-100635
- 3.Electrophysiological, biochemical, neurohormonal and behavioural studies with WAY-100635, a potent, selective and silent 5-HT1A receptor antagonist
- 4.Pharmacological characterization of recombinant human 5-hydroxytryptamine1A receptors using a novel antagonist radioligand, [3H]WAY-100635
- 5.The putative > 5-HT(1A) receptor antagonist, WAY 100635, has inverse agonist properties at cloned human 5-HT(1A) receptors.
- 6.Native rat hippocampal 5-HT1A receptors show constitutive activity
- 7.A retrospect on the discovery of WAY-100635 and the prospect for improved 5-HT(1A) receptor PET radioligands
- 8.Effects of 5-HT1A receptor antagonists on hippocampal 5-hydroxytryptamine levels: (S)-WAY100135, but not WAY100635, has partial agonist properties
- 9.WAY-100635 is a potent dopamine D4 receptor agonist
- 10.WAY-100635 has high selectivity for serotonin 5-HT(1A) versus dopamine D(4) receptors
- 11.WAY 100635 produces discriminative stimulus effects in rats mediated by dopamine D(4) receptor activation
- 12.Dopamine D4 receptor involvement in the discriminative stimulus effects in rats of LSD, but not the phenethylamine hallucinogen DOI
30 listed here; entry last updated August 2026
Reviews
My notesprivate to this device
FAQ
Is WAY-100635 something a person can take?
No. It has never been approved anywhere, has never been given to anyone as a medicine, and has no published human dose, pharmacokinetics or toxicology. It is sold for laboratory work only.
Was it ever meant to be a drug?
Yes, at the start. The Wyeth patent that first disclosed it, filed in 1991, claims the series for treating anxiety and lists antidepressant, antihypertensive, sleep and feeding uses alongside; the team's own 1993 review is titled around silent 5-HT1A antagonists being useful as research tools and therapeutic agents both [1]. By the time the first pharmacological profile appeared in 1995 the ambition had narrowed, and that paper closes by saying the compound will serve as a standard antagonist for studying the receptor [2]. It never entered clinical development for any indication.
So is it a selective 5-HT1A antagonist or not?
At the 5-HT1A receptor it is potent and it is silent, and that part is not disputed. Selectivity is disputed. A 2006 screen found low nanomolar binding and full agonist activity at dopamine D4 [9], and a 2007 rebuttal measured a much weaker partial effect and argued the selectivity is fine [10]. Rats trained on higher doses produce a drug cue that only D4 antagonists block [11], so the D4 action appears to be real in a living animal even though its potency is unsettled.
Does the D4 problem mean the old 5-HT1A literature is wrong?
Not wholesale, and dose is the reason. Blocking 5-HT1A in a rat has an ED50 near 0.03 mg/kg [8], while the dose at which D4 activation becomes behaviourally obvious is roughly two orders of magnitude higher [11]. A study using a low systemic dose is on much safer ground than one using a high dose or infusing the compound straight into a brain nucleus. The honest position is that each study has to be judged on the dose it actually used, which is a smaller problem than the 2006 warning implies and a much larger one than nothing.
Have humans ever been given this compound?
Yes, but only as a radioactive tracer. [carbonyl-11C]WAY-100635 has been injected into volunteers and patients for positron emission tomography since 1996 [17], and the technique is still in use [28]. The injected mass is about 1.5 to 3.0 micrograms [21], small enough to occupy only a fraction of the receptor and produce no drug effect. That is real human exposure, and no adverse event has ever been reported after one, but it says nothing about the safety of a pharmacologically active dose.
Is a PET scan with this tracer risky?
The risk that has actually been measured is radiation rather than pharmacology, and this tracer is at the high end. A dosimetry study in six volunteers found the urinary bladder wall to be the critical organ and found human absorbed doses roughly 6.6 times the rat estimate for kidney and 60.6 times the rat estimate for bladder wall, which is why a single injection is capped at 300 MBq in a man and 227 MBq in a woman, with at most three a year [20].
Why does the same compound look anxiolytic in one experiment and anxiogenic in another?
Because location changes the answer. Blocking postsynaptic 5-HT1A receptors and blocking the autoreceptor on raphe cell bodies have opposite consequences for serotonin tone, and the two raphe nuclei do not project to the same places. Infused into the median raphe of mice the compound increased open-arm exploration and cut risk assessment, an anxiolytic pattern, while the same infusion into the dorsal raphe did nothing; the authors argued the median raphe projection to the periaqueductal gray explains it [14]. Its founding paper had already reported anxiolytic-like effects in the mouse light and dark box [3].
Does WAY-100635 block noradrenaline reuptake?
There is no evidence for it. PubMed returns nothing for the compound or its metabolite against the noradrenaline transporter, and ChEMBL holds 192 bioactivity records for WAY-100635 without a single noradrenaline transporter measurement among them. It does bind alpha-1 adrenoceptors, which is a different thing and is probably the source of the confusion; that affinity is real, and the subtype-resolved values are tighter than the original description of it as moderate.
Why do depression imaging studies with this tracer disagree with each other?
Because the reference region is not clean. Of eight studies asking whether 5-HT1A binding is altered in major depression, four found a decrease, two found no change and two found an increase, and a review concluded the results cannot be pooled into an answer [22]. One paper made the mechanism plain by getting three different answers from a single dataset depending on whether cerebellar grey matter, cerebellar white matter or total distribution volume was used [23]. The cerebellum was assumed to hold no 5-HT1A receptors and it does.
Limitations of the evidence
- The selectivity claim is actively contested and has not been resolved. One laboratory reports potent full agonism at dopamine D4, another reports weak partial agonism and high selectivity, and neither result has been withdrawn
- No human pharmacokinetics, no toxicology package and no repeated-exposure data exist in the public record. The only human exposure is a microgram tracer mass in a PET scan, chosen so that it produces no drug effect, which proves nothing about an active dose
- Nearly the whole literature is animal and in vitro, and nearly all of it uses the compound as a reagent rather than studying the compound, so its own properties are far less examined than its citation count suggests
- The dopamine D4 problem is dose dependent rather than universal. It appears an order of magnitude or more above the dose needed to block 5-HT1A, so it threatens high-dose systemic work and direct brain infusions far more than ordinary low systemic doses, and each older study has to be judged on the dose it actually used
- A microinfusion of 3.0 micrograms into 0.1 microlitres of tissue produces a local concentration far outside any selectivity window measured in a test tube, which is exactly the condition under which a second receptor stops being hypothetical
- The cerebellum, used as the receptor-free reference region for most of the human imaging work, is not actually receptor free, and the resulting choice between cerebellar grey and cerebellar white matter can flip the sign of a published finding within a single dataset
- Claims that WAY-100635 or its metabolite block the noradrenaline transporter are not supported by anything findable, and there is affirmative evidence the other way. The original selectivity screen covered reuptake sites and reported more than a hundredfold selectivity across that panel; ChEMBL holds 192 bioactivity records for the compound and not one of them is a noradrenaline transporter measurement, and every serotonin transporter record is negative
- The word silent is not quite right in every system. WAY-100635 behaves as a neutral antagonist at native rat hippocampal 5-HT1A receptors but as a weak inverse agonist at cloned human receptors expressed at high density under low-sodium conditions, so a paper's claim about intrinsic activity depends on the preparation it was measured in
Adverse effects
- No human adverse-event profile exists at any pharmacologically active dose, because no pharmacologically active dose has ever been given to a person
- Dopamine D4 receptor activation, strong enough at higher doses for rats to recognise it as a distinct drug state that selective D4 antagonists abolish
- A brain-penetrant metabolite, WAY-100634, formed by cleavage of the amide bond, carrying its own activity at 5-HT1A receptors, alpha-1 adrenoceptors and dopamine D4
- Affinity at alpha-1 adrenoceptors, with subtype-resolved values as low as a few nanomolar at alpha-1D, close enough to the primary target to matter
- Effects that reverse direction depending on where the compound is put; infused into the median raphe it was anxiolytic in mice, the opposite of what autoreceptor blockade there predicts
- As a radiotracer the exposure of note is radiation rather than pharmacology, and the human absorbed dose turned out to be far higher than the rodent estimate had suggested, with the urinary bladder wall as the critical organ
Notes and cautions
- Three very similar names sit close together and are routinely confused. WAY-100135 is the earlier Wyeth compound and is a partial agonist rather than a silent antagonist; WAY-100635 is this compound; WAY-100634 is this compound's brain-penetrant metabolite, formed by cleavage of the amide bond.
- The documented off-target activity of the metabolite WAY-100634 is at 5-HT1A receptors and alpha-1 adrenoceptors, plus dopamine D4. No evidence was found in PubMed, in ChEMBL or in any secondary source that it blocks the noradrenaline transporter, and that claim should be treated as unsupported until a primary source appears.
- Identifiers, because they are unusually messy here. Free base: PubChem CID 5684, ChEMBL31354, CAS 162760-96-5, UNII 71IH826FEG, formula C25H34N4O2, molecular weight 422.57. The molecule is achiral. It is always supplied as a salt, and the salt changed: every original Wyeth paper used the trihydrochloride (CAS 146714-97-8), while what is sold today is the maleate, which itself circulates under two different CAS numbers depending on the supplier. That is why quoted molecular weights differ between catalogues.
- Searching ChEMBL by name fails for this compound. Its preferred name there is written with a comma, as WAY-100,635, so both WAY-100635 and WAY100635 return nothing; a structure search finds it. The same record also carries a natural-product flag, which is wrong, since the molecule is entirely synthetic.
- It is not a controlled substance in the United States; a search of the current text of the federal schedules finds no entry for it under any spelling. Whether any other jurisdiction schedules it was not established. It has never been approved as a medicine anywhere, holds no clinical development phase in ChEMBL, and appears in no United States drug label database.
- The position of the carbon-11 label is not a detail. The first version put it on the methoxy group, and because the amide bond is cleaved to a brain-penetrant fragment the label followed that fragment into the brain and confounded the signal. Moving it to the cyclohexanecarbonyl group put it on the piece that leaves rather than the piece that stays, which is why the useful tracer is specifically [carbonyl-11C]WAY-100635.
- The compound appears in the clinical trials registry only as an imaging agent, never as an intervention. The single completed Phase 1 record using it is a receptor-occupancy study of a different molecule.
- Robalzotan (NAD-299) is the closest compound in this catalogue conceptually: the same autoreceptor-antagonist idea taken into a clinical trial, where it failed, and also developed into a PET ligand for the same receptor.
- The parent compound behaved as an anxiolytic in its own founding paper, in the mouse light and dark box, which is worth remembering before treating any single anxiolytic result with this compound as surprising.