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Vanilloid
Vanilloid
Vanilloid
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The vanilloids are compounds which possess a vanillyl group. They include vanillyl alcohol, vanillin, vanillic acid, acetovanillon, vanillylmandelic acid, homovanillic acid, capsaicin, etc. Isomers are the isovanilloids.

Structure of vanillyl alcohol Structure of Vanillin Structure of vanillic acid Structure of acetovanillon Structure of vanillylamine Structure of Capsaicin
vanillyl alcohol vanillin vanillic acid acetovanillon Vanillylamine Capsaicin

A number of vanilloids, most notably capsaicin, bind to the transient receptor potential vanilloid type 1 (TRPV1) receptor, an ion channel which naturally responds to noxious stimuli such as high temperatures and acidic pH.[1] This action is responsible for the burning sensation experienced after eating spicy peppers. Endogenously generated chemicals that trigger the TRPV1 channel of the vanilloids class are referred to as endovanilloids[2] including anandamide, 20-hydroxyeicosatetraenoic acid (20-HETE),[3] N-arachidonoyl dopamine (NADA) and N-oleoyl-dopamine (CID 5282106 from PubChem).[4]

Fatty acid amide hydrolase (FAAH), is a crucial enzyme for endovanilloid, and the N-acylethanolamines (NAEs), catabolism at TRPV1, and other cannabinoid receptors.[5]

Structure of Anandamide
Anandamide

Outside the food industry vanilloids such as nonivamide are used commercially in pepper spray formulations.

Other vanilloids which act at TRPV1 include resiniferatoxin and olvanil.[6]

References

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Literature

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Vanilloid

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Vanilloids are a class of organic compounds characterized by the presence of a vanillyl group (4-hydroxy-3-methoxybenzyl) in their molecular structure, encompassing both natural and synthetic substances derived from various sources such as and fungi. The prototypical example is , the lipophilic responsible for the pungent heat in chili peppers ( species), which structurally features an amide-linked vanillyl moiety to a hydrophobic alkyl chain. These compounds are renowned for their interaction with the transient receptor potential vanilloid 1 () , a polymodal primarily expressed in primary afferent nociceptors of the peripheral . Activation of by vanilloids such as or the ultrapotent analog (RTX) elicits an influx of cations, leading to neuronal , excitation, and subsequent sensations of burning , warmth, and neurogenic . Beyond capsaicinoids, vanilloids include diverse classes like unsaturated dialdehydes (e.g., polygodial from Polygonum hydropiper) and triprenyl phenols (e.g., scutigeral from Albatrellus scutiger), which also bind but vary in potency and . Pharmacologically, vanilloids have been studied for their dual effects: initial activation followed by desensitization and defunctionalization of TRPV1-expressing neurons, offering potential as non-opioid analgesics for conditions like chronic , , and . Synthetic vanilloid derivatives, such as olvanil and arvanil, have been developed to enhance selectivity and reduce pungency, while endogenous vanilloids like contribute to endocannabinoid-vanilloid crosstalk in pain modulation. Despite their therapeutic promise, challenges include dose-dependent toxicity and off-target effects on cardiovascular and gastrointestinal systems.

Chemistry

Definition and Chemical Structure

Vanilloids constitute a class of organic compounds defined by the presence of a vanillyl group, specifically the 4-hydroxy-3-methoxybenzyl moiety (C₈H₉O₃), which is structurally derived from through the phenylpropanoid biosynthetic pathway. This features a ring with a hydroxyl at the 4-position and a at the 3-position relative to the methylene linker, enabling attachment to diverse side chains that modulate the compound's overall properties. The core vanillyl structure imparts key physicochemical characteristics to vanilloids, including high due to the aromatic and alkyl components, which facilitates in fats, oils, and alcohols (e.g., ) while resulting in low aqueous (typically <0.1 mg/mL for representative members). These compounds also demonstrate thermal stability, remaining intact under standard cooking temperatures up to approximately 200°C, though prolonged exposure to higher heat can lead to gradual decomposition. The vanillyl group's configuration is critical for the characteristic pungency observed in many vanilloids, stemming from its precise molecular interactions that underlie sensory activation. In capsaicinoids, a prominent subclass, the vanillyl group links via an amide bond to a branched, unsaturated alkyl chain, as illustrated by the general formula for capsaicin: (E)-N-(4-hydroxy-3-methoxybenzyl)-8-methylnon-6-enamide (C₁₈H₂₇NO₃). This arrangement exemplifies how side-chain variations influence lipophilicity and stability without altering the defining vanillyl core. Isovanilloids represent structural isomers distinguished by the transposition of the hydroxyl and methoxy substituents, yielding a 3-hydroxy-4-methoxybenzyl group instead of the standard vanillyl configuration. This positional swap alters the electronic properties of the aromatic ring, potentially affecting reactivity and binding affinity while preserving the overall benzyl framework.

Synthetic and Natural Vanilloids

Vanilloids encompass a diverse class of compounds characterized by the presence of the vanillyl group, with notable examples derived from both natural botanical sources and synthetic production methods. Among natural vanilloids, capsaicin stands out as the primary pungent compound isolated from fruits of the genus within the family, particularly chili peppers such as . , an ultrapotent vanilloid, is a phorbol-related diterpene isolated from the resin of the Moroccan plant in the family, featuring a homovanillyl group. Synthetic vanilloids include nonivamide, a direct analog of capsaicin produced through chemical synthesis to replicate its structure for industrial applications, such as in pepper sprays and food additives. Olvanil, featuring a longer unsaturated fatty acid chain, serves as a research-oriented analog of capsaicin, synthesized to explore structural variations while maintaining the vanillyl amide core. Additional vanilloids related to metabolic processes include vanillyl alcohol and homovanillic acid, which function as biomarkers in human urine for assessing catecholamine metabolism and detecting conditions like neuroblastoma. Vanillylmandelic acid, with a modified linker, is similarly used as a biomarker. These compounds arise from the breakdown of neurotransmitters and are structurally linked to the vanillyl motif. Capsaicinoids, including capsaicin, originate botanically from the placental tissues of fruits in the Solanaceae family and are typically extracted using solvents like ethanol or supercritical CO2 to isolate them from pepper waste or dried fruits. Synthetic analogs of vanilloids are commonly prepared via amide coupling reactions, where vanillylamine is reacted with carboxylic acids or their derivatives using coupling agents such as PyBOP to form the characteristic amide linkage.

Biology and Physiology

TRPV1 Receptor Interaction

The transient receptor potential vanilloid 1 () receptor is a non-selective cation channel predominantly expressed in primary sensory neurons, where it functions as a key integrator of noxious stimuli. As a member of the TRP channel family, TRPV1 permits the influx of monovalent and divalent cations, including calcium (Ca²⁺), upon activation. It is gated by multiple modalities, including vanilloids such as capsaicin, temperatures exceeding 43°C, and extracellular protons at pH below 6, thereby contributing to the detection of thermal and chemical pain signals. TRPV1 is primarily expressed in small- to medium-diameter nociceptive neurons of the dorsal root ganglia (DRG) and trigeminal ganglia, which innervate peripheral tissues. Beyond these sensory sites, lower levels of expression occur in non-neuronal tissues such as the urinary bladder urothelium and detrusor muscle, as well as epidermal keratinocytes in the skin, where it modulates local inflammatory responses. In the central nervous system, TRPV1 shows restricted expression in discrete brain regions, including the hypothalamus and substantia nigra, contrasting with its more abundant peripheral distribution. Vanilloids interact with TRPV1 through binding to an intracellular vanilloid pocket formed by residues in the transmembrane segments S3 and S4, as well as the S4-S5 linker. This binding induces conformational changes that widen the channel pore, facilitating Ca²⁺ influx and subsequent depolarization of the neuron. Activation leads to rapid desensitization, primarily driven by Ca²⁺-dependent mechanisms that involve calmodulin binding and phosphatase activity, though phosphorylation by kinases such as protein kinase C (PKC) and protein kinase A (PKA) at specific serine and threonine residues modulates this process by reducing desensitization and enhancing channel sensitivity. Cryo-electron microscopy (cryo-EM) structures have elucidated the molecular basis of vanilloid binding, revealing that capsaicin, a prototypical vanilloid, occupies a pocket adjacent to the S4-S5 linker. In the capsaicin-bound state, the vanillyl hydroxyl group forms hydrogen bonds with receptor residues, including tyrosine and serine side chains, while the amide tail engages hydrophobic interactions, stabilizing the open conformation through a "pull-and-contact" mechanism that repositions the S4-S5 linker. These insights, derived from high-resolution structures at near-physiological temperatures, highlight how vanilloid binding synergizes with other activators to promote channel gating.

Endogenous Vanilloids and Signaling Pathways

Endogenous vanilloids, also known as endovanilloids, are internally produced lipid molecules that act as ligands for the channel, distinct from exogenous compounds like . These molecules include (N-arachidonoylethanolamide), N-arachidonoyl dopamine (NADA), N-oleoyl dopamine, and 20-hydroxyeicosatetraenoic acid (20-HETE). is biosynthesized from N-arachidonoylphosphatidylethanolamine via calcium-dependent N-acyl phosphatidylethanolamine phospholipase D, while NADA and N-oleoyl dopamine arise from the conjugation of arachidonic acid or oleic acid with dopamine, potentially through uncharacterized enzymes. 20-HETE is generated from arachidonic acid by cytochrome P450 ω-hydroxylases. Lipoxygenase enzymes, such as those producing 12(S)- or 15(S)-hydroperoxyeicosatetraenoic acid (HPETE), also contribute to endovanilloid formation from arachidonic acid released by . Upon binding to TRPV1, endovanilloids activate the channel, leading to cation influx and downstream signaling cascades critical for nociception. This activation triggers protein kinase C (PKC)-mediated phosphorylation of TRPV1, which sensitizes the receptor and initiates the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway, promoting neuronal excitability and pain signaling. There is notable crosstalk between TRPV1 and cannabinoid type 1 (CB1) receptors, as anandamide and NADA act as dual ligands; CB1 activation can modulate TRPV1 responses, facilitating endogenous pain control by balancing pronociceptive and antinociceptive effects in sensory neurons. In inflammatory contexts, endovanilloid-induced TRPV1 activation contributes to cytokine release, such as substance P and calcitonin gene-related peptide, amplifying neurogenic inflammation. Regulation of endovanilloid levels is primarily mediated by fatty acid amide hydrolase (FAAH), which hydrolyzes anandamide into arachidonic acid and ethanolamine, thereby controlling TRPV1 tone and preventing excessive activation. FAAH inhibition elevates anandamide levels, enhancing TRPV1-mediated responses, while NADA and 20-HETE are inactivated by methylation or reduction, respectively. Physiologically, endovanilloids play roles in thermoregulation by modulating heat responses via TRPV1 in sensory neurons, influencing body temperature maintenance. In visceral sensation, they contribute to bladder and bronchial contractility; for instance, NADA induces contractions in isolated guinea pig bronchi and urinary bladder similar to capsaicin. Additionally, they support endogenous pain modulation, with NADA promoting thermal hyperalgesia and anandamide alleviating neuropathic pain through balanced TRPV1-CB1 signaling.

Pharmacology

Agonists, Antagonists, and Mechanisms

Vanilloids primarily exert their effects through activation of the transient receptor potential vanilloid 1 (TRPV1) channel, with agonists such as and resiniferatoxin (RTX) serving as key pharmacological tools. , derived from chili peppers, acts as a partial agonist at TRPV1, binding to the vanilloid site in the channel's transmembrane domain and eliciting channel opening with an EC50 of approximately 0.7 μM. RTX, a naturally occurring ultra-potent analog from the plant, functions as a full agonist at the same site, demonstrating roughly 1000-fold greater potency than due to stronger interactions with the binding pocket, leading to more sustained channel activation. Both agonists initially trigger rapid influx of cations, including Ca2+, causing neuronal excitation and firing; however, prolonged exposure results in desensitization through Ca2+ overload, which promotes channel , internalization, and temporary refractoriness to further stimulation. Antagonists of are classified by their binding modes and include competitive, non-competitive, and s. represents a prototypical competitive , binding directly to the vanilloid site to sterically hinder access and prevent channel gating by capsaicin or . In contrast, ruthenium red acts as a non-competitive pore blocker, occluding the channel's pathway without interacting with the -binding site, thereby inhibiting Ca2+ influx evoked by diverse stimuli. SB-366791, an , binds within the vanilloid pocket but induces conformational changes that stabilize the closed state of the channel, effectively inhibiting activation by s, protons, or with high selectivity for human over related isoforms. The pharmacological actions of vanilloid agonists exhibit dose-dependent biphasic effects on TRPV1-expressing neurons: low concentrations (e.g., sub-micromolar ) enhance channel sensitivity via by kinases like PKC, leading to and amplified responses to or chemical stimuli, whereas high doses (e.g., micromolar to millimolar) induce defunctionalization through exhaustive Ca2+-dependent desensitization, , and long-term neuronal silencing. Pharmacokinetically, undergoes rapid hepatic metabolism primarily via cytochrome P450 enzymes such as and , yielding dehydrogenated metabolites that reduce but limit systemic exposure and duration of action. TRPV1 displays notable selectivity among transient receptor potential vanilloid family members; for instance, potently activates at physiological temperatures but fails to engage TRPV2, which requires higher heat thresholds (>52°C) for activation without responsiveness to vanilloids. This distinction arises from structural differences in the ligand-binding domains, underscoring 's specialized role in chemical and moderate thermal .

Therapeutic Applications and Clinical Uses

Vanilloids, particularly , have established clinical applications in through their interaction with receptors, leading to temporary defunctionalization of nociceptive fibers. The 8% patch (Qutenza) is FDA-approved since 2009 for treating associated with , applied topically for 60 minutes to affected areas, providing relief lasting 3 to 6 months via selective ablation of pain-transmitting C-fibers. In 2020, the FDA expanded approval to include from diabetic peripheral neuropathy in the feet, demonstrating sustained efficacy in reducing pain intensity. Clinical evidence from randomized controlled trials supports moderate pain relief with the 8% patch, with meta-analyses of 25 RCTs showing 30% to 50% reductions in pain scores compared to for various peripheral neuropathic conditions. Common side effects include transient burning sensation during application, which can be mitigated by pre-treating the skin with lidocaine. A Cochrane review confirms that about 10% more patients achieve at least 30% pain reduction over 2 to 12 weeks with versus . Beyond , intranasal has shown prophylactic benefits for cluster headaches, with repeated applications desensitizing endings and reducing attack frequency in double-blind trials. , a potent vanilloid agonist, is under investigation for other indications; intravesical administration has demonstrated efficacy in restoring continence and reducing in patients with detrusor overactivity, including idiopathic and neurogenic cases. For , intra-articular injections are in Phase III trials, including an ongoing randomized, double-blind study (NCT05248386), for moderate to severe , targeting TRPV1-positive afferents to provide long-term analgesia; the program received FDA designation in 2023. Emerging therapeutic strategies involve TRPV1 antagonists and endovanilloid modulation. NEO6860, a modality-selective TRPV1 antagonist that blocks capsaicin activation without affecting heat or pH responses, showed analgesic effects in a Phase II proof-of-concept trial for osteoarthritis knee pain, reducing pain scores without common hyperthermia side effects seen in broader antagonists. Fatty acid amide hydrolase (FAAH) inhibitors, which elevate endogenous vanilloids like anandamide, are being explored for anxiety and depression; preclinical and early clinical data suggest anxiolytic effects by enhancing endocannabinoid signaling, though large-scale trials are ongoing. As of November 2025, a Phase III trial (AV001) for Qutenza in post-surgical neuropathic pain has completed recruitment, with topline results expected in late 2025. Limitations include variable response rates and the need for specialized administration, emphasizing the importance of patient selection in clinical practice.

History and Research

Discovery and Early Studies

The use of chili peppers, the primary natural source of vanilloids such as , dates back to pre-Columbian times in the , where they were cultivated and employed as spices and in for ailments including and digestive issues. Archaeological evidence from sites in confirms their consumption and medicinal application spanning over 6,000 years, predating European contact. Following the in the 16th century, chili peppers spread globally, integrating into systems like in , where capsaicin-containing preparations were used topically for relief in conditions such as and . The scientific discovery of vanilloids began in the early with the isolation of , the prototypical vanilloid, from cayenne peppers () by German chemist Christian Friedrich Bucholz in 1816, though initially in impure form. Subsequent efforts advanced purification; in 1876, John Clough Thresh extracted a nearly pure crystalline form and coined the name "," derived from the genus . By the 1920s, the was elucidated through work by E.K. Nelson, who identified it as (E)-N-(4-hydroxy-3-methoxybenzyl)-8-methylnon-6-enamide, establishing its vanillyl amide framework essential for . Early biological studies in the mid-20th century revealed capsaicin's effects on the . In the , Hungarian pharmacologist Jancsó demonstrated its neurotoxic properties, showing that systemic administration in newborn rats caused selective degeneration of primary sensory neurons, particularly unmyelinated C-fibers involved in pain transmission, without affecting motor neurons. This finding highlighted capsaicin's potential as a tool for studying sensory . Building on this, in 1990, Arpád Szallasi and Peter M. Blumberg coined the term "vanilloid receptor" to describe the specific binding site for and related compounds like on membranes. A pivotal milestone came in 1997 when Michael J. Caterina and colleagues cloned the capsaicin receptor from rat sensory neurons using expression cloning in HEK293 cells, identifying it as VR1—a heat-activated, non-selective cation channel responsive to temperatures above 43°C, protons, and vanilloids. Published in Nature, this discovery linked vanilloids mechanistically to nociception, paving the way for understanding their role in pain signaling while confirming the receptor's distribution in small-diameter sensory neurons.

Modern Developments and Future Directions

Following the cloning of the TRPV1 receptor in the late 1990s, studies using knockout mice from the early 2000s onward have elucidated its critical roles in modulating , demonstrating reduced inflammatory responses in models of and , which has informed targeted therapies for chronic inflammatory conditions. High-resolution cryo-electron microscopy structures of , achieved in 2013 at 3.4 Å resolution, have revealed the channel's tetrameric architecture and ligand-binding sites, facilitating structure-based for selective vanilloid modulators. In the 2020s, research has expanded vanilloid applications to emerging areas. Studies on have shown that ultra-potent agonists like reduce tumor-associated in models by desensitizing TRPV1-expressing afferents, with phase I trials demonstrating safety for . Additionally, capsaicin-induced increases in energy expenditure have been linked to enhanced and potential benefits in human studies of . FAAH inhibitors have been investigated in clinical trials for various pain conditions, including . By 2024–2025, further advances include exploration of -targeted therapies for , such as agonists to silence pain-sensing nerves in tumors, and for with novel ligands. Research has also shown activation reduces sepsis-associated brain injury in models by inhibiting . Integration of in ligand screening has accelerated discovery, with models predicting high-affinity vanilloid binders to , enhancing hit rates in virtual libraries by over 50% in recent computational studies. Despite these advances, challenges persist, particularly with off-target effects of antagonists, which often induce by disrupting central thermoregulatory circuits, as observed in multiple clinical candidates that failed phase II due to body temperature elevations exceeding 1°C. Regulatory hurdles for ultra-potent agonists like include stringent safety requirements for neurotoxic potential and delivery methods, delaying FDA approval despite orphan drug designation for . Looking ahead, approaches modulating expression, such as AAV-delivered shRNA for silencing in sensory neurons, hold potential for long-term pain relief in chronic conditions without systemic side effects. Furthermore, modulators are under investigation for roles in autoimmune diseases and disorders.

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