Mirogabalin: a novel gabapentinoid or another false dawn?

PURPOSE OF REVIEW: Mirogabalin is a novel gabapentinoid medication for the treatment of neuropathic pain. The purpose of this review is to discuss current evidence for its use. Gabapentinoids are widely prescribed for neuropathic pain. Mirogabalin offers theoretical advantages over traditional gabapentinoids due to its specificity for the α2δ-1 subunit of voltage-gated calcium channels. It is theorised that this specificity may reduce adverse drug reactions by minimising binding to the α2δ-2 subunit which is responsible for many of the gabapentinoid side effects. RECENT FINDINGS: Mirogabalin's slower dissociation from the α2δ-1 compared with α2δ-2, and its higher potency may also impart an efficacy benefit over traditional gabapentinoids. These theoretical advantages of mirogabalin remain inconclusive in clinical practice, with mixed evidence regarding mirogabalin versus traditional gabapentinoids. Some studies suggest a reduced side effect profile yet, others fail to demonstrate significant differences. Regarding efficacy, mirogabalin may be superior to placebo for several neuropathic pain syndromes, but evidence of widespread benefit over traditional gabapentinoids is currently lacking. SUMMARY: Mirogabalin offers theoretical promise, but large, independent studies are required to further assess its performance versus traditional gabapentinoids.

Occurrence of somnolence and respiratory depression induced by pregabalin and mirogabalin use and the influence of opioid treatment using the Japanese adverse drug event report database.

Background: Gabapentinoid anticonvulsants are standard treatment for neuropathic pain and are often combined with opioids for treating cancer. It is assumed that this combination may heighten somnolence and respiratory depression due to the inhibitory effects of opioids on the central nervous system. Although pregabalin, a gabapentinoid, is known to increase somnolence frequency during opioid therapy, whether mirogabalin exerts similar effects on somnolence frequency under opioid therapy remains unknown. This study examined the signals of somnolence and respiratory depression in response to pregabalin and mirogabalin use by utilizing data from the Japanese Adverse Drug Event Report database and assessed their interaction with strong opioid analgesics. Methods: Information was obtained from the JADER database from April 2004 to August 2023 via the Pharmaceuticals and Medical Devices Agency website. The study focused on neuropathic pain medications, specifically "pregabalin" and "mirogabalin besilate." Adverse events were defined using preferred terms (PTs) from the Medical Dictionary for Regulatory Activities version 26.1. The PTs considered were "Somnolence (10041349)" and "Respiratory depression (10038678)." To investigate the effect of the combination of strong opioid analgesics with pregabalin and mirogabalin on the occurrence of somnolence, a multivariable logistic regression analysis was conducted. Results: Signals for somnolence were detected with the use of both drugs (pregabalin: information component (IC) [95% confidence intervals (CIs)]: 2.89 [2.70 to 3.08]; mirogabalin: IC [95% CIs] 2.50 [1.85 to 3.16]). When evaluating respiratory depression, a typical and serious adverse event of opioid analgesic use, a signal was detected with pregabalin use but not with mirogabalin use (pregabalin: (IC [95% CIs] 1.28 [0.83 to 1.73]; mirogabalin: IC [95% CIs] -0.15 [-2.20 to 1.89]). Multivariable analysis indicated that the use of strong opioid analgesics increased the occurrence of somnolence when combined with pregabalin but not when combined with mirogabalin (p = 0.004). Conclusion: While the safety of concomitant administation of mirogabalin with opioids remains controversial, caution should be exercised when using pregabalin, especially in combination with opioids for neuropathic pain, compared to that for mirogabalin.

Activation of α7 nicotinic receptors attenuated hyperalgesia and anxiety induced by palatable obesogenic diet withdrawal.

Consumption of palatable food (PF) can alleviate anxiety, and pain in humans. Contrary, spontaneous withdrawal of long-term PF intake produces anxiogenic-like behavior and abnormal pain sensation, causing challenges to weight-loss diet and anti-obesity agents. Thus, we examined α7-nicotinic acetylcholine receptors (α7nAChR) involvement since it plays essential role in nociception and psychological behaviors. METHODS: Adult male C57BL/6 mice were placed on a Standard Chow (SC) alone or with PF on intermittent or continuous regimen for 6 weeks. Then, mice were replaced with normal SC (spontaneous withdrawal). Body weight, food intake, and calories intake with and without the obesogenic diet were measured throughout the study. During PF withdrawal, anxiety-like behaviors and pain sensitivity were measured with PNU-282987 (α7nAChR agonist) administration. RESULTS: Six weeks of SC + PF-intermittent and continuous paradigms produced a significant weight gain. PF withdrawal displayed hyperalgesia and anxiety-like behaviors. During withdrawal, PNU-282987 significantly attenuated hyperalgesia and anxiety-like behaviors. CONCLUSION: The present study shows that a PF can increase food intake and body weight. Also, enhanced pain sensitivity and anxiety-like behavior were observed during PF withdrawal. α7nAChR activation attenuated anxiolytic-like behavior and hyperalgesia in PF abstinent mice. These data suggest potential therapeutic effects of targeting α7 nAChRs for obesity-withdrawal symptoms in obese subjects.

Impairment of brain function in a mouse model of Alzheimer's disease during the pre-depositing phase: The role of α7 nicotinic acetylcholine receptors.

Alzheimer's disease (AD) is an age-dependent incurable neurodegenerative disorder accompanied by neuroinflammation, amyloid accumulation, and memory impairment. It begins decades before the first clinical symptoms appear, and identifying early biomarkers is key for developing disease-modifying therapies. We show now in a mouse model of AD that before any amyloid deposition the brains of 1.5-month-old mice contain increased levels of pro-inflammatory cytokines IL-1ß and IL-6, decreased levels of nicotinic acetylcholine receptors (nAChRs) in the brain and brain mitochondria and increased amounts of α7 nAChR-bound Aß1-42, along with impaired episodic memory and increased risk of apoptosis. Both acute (1-week-long) and chronic (4-month-long) treatments with α7-selective agonist PNU282987, starting at 1.5 months of age, were well tolerated. The acute treatment did not affect the levels of soluble Aß1-42 but consistently upregulated the α7 nAChR expression, decreased the level of α7-Aß1-42 complexes, and improved episodic memory of 1.5-month-old mice. The chronic treatment, covering the disease development phase, strongly upregulated the expression of all abundant brain nAChRs, reduced both free and α7-coupled Aß1-42 within the brain, had anti-inflammatory and antiapoptotic effects, and potently upregulated cognition, thus identifying α7 nAChRs as both early biomarker and potent therapeutic target for fighting this devastating disease.

Determinants of interactions of a novel next-generation gabapentinoid NVA1309 and mirogabalin with the Cavα2δ-1 subunit.

NVA1309 is a non-brain penetrant next-generation gabapentinoid shown to bind Cavα2δ at R243 within a triple Arginine motif forming the binding site for gabapentin and pregabalin. In this study we have compared the effects of NVA1309 with Mirogabalin, a gabapentinoid drug with higher affinity for the voltage-gated calcium channel subunit Cavα2δ-1 than pregabalin which is approved for post-herpetic neuralgia in Japan, Korea and Taiwan. Both NVA1309 and mirogabalin inhibit Cav2.2 currents in vitro and decrease Cav2.2 plasma membrane expression with higher efficacy than pregabalin. Mutagenesis of the classical binding residue arginine R243 and the newly identified binding residue lysine K615 reverse the effect of mirogabalin on Cav2.2 current, but not that of NVA1309.

Evaluation of the Potential Beneficial Effects of Ferula communis L. Extract Supplementation in Postmenopausal Discomfort.

Peri-menopausal discomfort can have a detrimental effect on the physical health of women due to physiological and behavioral changes. Estrogen and progesterone-based hormone therapy can alleviate menopausal symptoms, but estrogen supplementation may have negative health effects. The effectiveness of hormone replacement therapy using natural compounds for peri-menopausal disorders is still uncertain. Evidence from in vivo experiments indicates that Ferula L. extract in ovariectomized rats leads to better sexual behavior. The effect seems to be linked to the phytoestrogenic properties of ferutinin, the primary bioactive compound in the extract. The purpose of this study was to assess the clinical impact of Ferula communis L. extract (titrated at 20% ferutinin, and given at doses of 100 mg/die for 90 days) on the quality of life of 64 menopausal women. The clinical trial was randomized, double-blind, and placebo controlled. Our data showed that Ferula communis L. extract reduced by 67 + 9% all symptoms associated to postmenopausal discomfort and enhanced significantly sexual behavior. In addition, the supplement led to a significant improvement of BMI and oxidative stress decrease in the women who received it, while also keeping platelet aggregation within normal levels. Overall, these results could point to the potential use of supplementation with Ferula communis L. extract to revert or mitigate menopause dysfunction.

Combined antiallodynic effects of Neurotropin®-tramadol and Neurotropin®-mirogabalin in rats with L5-spinal nerve ligation.

We aimed to examine the efficacy of combination therapies of Neurotropin® with tramadol and Neurotropin with mirogabalin for neuropathic pain management. A neuropathic pain model (L5 spinal nerve ligation model: L5-SNL) using male Wistar rats was generated through tight ligation of the left fifth lumbar nerve using silk sutures. Mechanical allodynia was assessed using the 50% paw withdrawal threshold. The combined antiallodynic effects were evaluated using isobolographic analyses. Small intestinal transit was evaluated using the charcoal meal test, and motor coordination using the rota-rod test. Neurotropin (50-200 NU/kg, p.o.), tramadol (7.5-60 mg/kg, p.o.), and mirogabalin (3-30 mg/kg, p.o.) showed a dose-dependent antiallodynic effect in L5-SNL rats. The combined antiallodynic effects of Neurotropin and tramadol were additive or synergistic, whereas those of Neurotropin and mirogabalin were additive. Neurotropin (100-400 NU/kg, p.o.) did not affect the small intestinal transit, whereas tramadol (30-100 mg/kg, p.o.) significantly inhibited it. Neurotropin (100-400 NU/kg, p.o.) did not affect the walking time, whereas mirogabalin (10-100 mg/kg, p.o.) significantly decreased it. Neurotropin dose-dependently ameliorated mechanical allodynia in rats, and combination therapy with Neurotropin-tramadol or Neurotropin-mirogabalin may alleviate neuropathic pain without aggravating the adverse effects of tramadol and mirogabalin.

mGlu2/3 receptor agonist (LY354740) in anxiety.

mGlu2/3 Receptors (LY354740) in Anxiety mGlu2/3 receptors when activated decrease glutamate excitation on limbic synapses involved in anxiety. The orally active agonist compound LY354740 (or prodrug LY544344) was active in animal and human models of stress/anxiety. Later clinical studies showed efficacy in generalized anxiety in patients, validating this mechanism clinically. However, the compound was terminated due to rodent seizures in long-term toxicology studies.

Biosynthesis of the Sesquiterpenoid Malfilanol D in Aspergillus ustus Implies Alkyl and Hydride Migrations during the Bicyclo[5.4.0]undecane Skeleton Formation.

The great variety and fascinating complexity of terpenoid skeletons are achieved through different cyclizations catalyzed by terpene cyclases. Here, we report a sesquiterpene cyclase (MfdS) from Aspergillus ustus for the formation of malfilanol D, a member of the group of biochemically less investigated sesquiterpenes with a bicyclo[5.4.0]undecane skeleton. Feeding 13C-labeled acetates in Aspergillus nidulans with the mfdS sequence provides evidence for a C-1 to C-10 cyclization with subsequent 1,2-alkyl and 1,2-hydride shifts in the formation of the 6/7-fused rings.

The human-specific nicotinic receptor subunit CHRFAM7A reduces α7 receptor function in human induced pluripotent stem cells-derived and transgenic mouse neurons.

We investigated the impact of the human-specific gene CHRFAM7A on the function of α7 nicotinic acetylcholine receptors (α7 nAChRs) in two different types of neurons: human-induced pluripotent stem cell (hiPSC)-derived cortical neurons, and superior cervical ganglion (SCG) neurons, taken from transgenic mice expressing CHRFAM7A. dupα7, the gene product of CHRFAM7A, which lacks a major part of the extracellular N-terminal ligand-binding domain, co-assembles with α7, the gene product of CHRNA7. We assessed the receptor function in hiPSC-derived cortical and SCG neurons with Fura-2 calcium imaging and three different α7-specific ligands: PNU282987, choline, and 4BP-TQS. Given the short-lived open state of α7 receptors, we combined the two orthosteric agonists PNU282987 and choline with the type-2 positive allosteric modulator (PAM II) PNU120596. In line with different cellular models used previously, we demonstrate that CHRFAM7A has a major impact on nicotinic α7 nAChRs by reducing calcium transients in response to all three agonists.

Macrophage α7nAChR alleviates the inflammation of neonatal necrotizing enterocolitis through mTOR/NLRP3/IL-1ß pathway.

BACKGROUND: Neonatal necrotizing enterocolitis (NEC) is one of the most prevalent and severe intestinal emergencies in newborns. The inflammatory activation of macrophages is associated with the intestinal injury of NEC. The neuroimmune regulation mediated by α7 nicotinic acetylcholine receptor (α7nAChR) plays an important role in regulating macrophage activation and inflammation progression, but in NEC remains unclear. This study aims to explore the effect of macrophage α7nAChR on NEC. METHODS: Mice NEC model were conducted with high-osmolarity formula feeding, hypoxia, and cold stimulation. The α7nAChR agonist PNU-282987 and mTOR inhibitor rapamycin were treated by intraperitoneal injections in mice. The expression and distribution of macrophages, α7nAChR, and phospho-mammalian target of rapamycin (p-mTOR) in the intestines of NEC patients and mice was assessed using immunohistochemistry, immunofluorescence, and flow cytometry. The expression of NLRP3, activated caspase-1 and IL-1ß in mice intestines was detected by flow cytometry, western blot or ELISA. In vitro, the mouse RAW264.7 macrophage cell line was also cultured followed by various treatments. Expression of p-mTOR, NLRP3, activated caspase-1, and IL-1ß in macrophages was determined. RESULTS: Macrophages accumulated in the intestines and the expression of α7nAChR in the mucosal and submucosal layers of the intestines was increased in both the NEC patients and mice. The p-mTOR and CD68 were increased and co-localized in intestines of NEC patients. In vitro, α7nAChR agonist PNU-282987 significantly reduced the increase of NLRP3, activated caspase-1, and IL-1ß in macrophages. PNU-282987 also significantly reduced the increase of p-mTOR. The effect was blocked by AMPK inhibitor compound C. The expression of NLRP3, activated caspase-1, and IL-1ß was inhibited after mTOR inhibitor rapamycin treatment. In NEC model mice, PNU-282987 reduced the expression of p-mTOR, NLRP3, activated caspase-1, and IL-1ß in the intestine. Meanwhile, rapamycin significantly attenuated NLRP3 activation and the release of IL-1ß. Moreover, the proportion of intestinal macrophages and intestinal injury decreased after PNU-282987 treatment. CONCLUSION: Macrophage α7nAChR activation mitigates NLRP3 inflammasome activation by modulating mTOR phosphorylation, and subsequently alleviates intestinal inflammation and injury in NEC.

Synthesis of (2R,4S)-4-Amino-5-hydroxybicyclo[3.1.1]heptane-2-carboxylic Acid via an Asymmetric Intramolecular Mannich Reaction.

Inhibition of human ornithine aminotransferase interferes with glutamine and proline metabolism in hepatocellular carcinoma, depriving tumors of essential nutrients. A proposed mechanism-based inhibitor containing a bicyclo[3.1.1]heptanol warhead is reported herein. The proposed inactivation mechanism involves a novel α-iminol rearrangement. The synthesis of the proposed inhibitor features an asymmetric intramolecular Mannich reaction, utilizing a chiral sulfinamide. This study presents a novel approach toward the synthesis of functionalized bicyclo[3.1.1]heptanes and highlights an underutilized method to access enantiopure exocyclic amines.

α7 nicotinic receptor activation mitigates herpes simplex virus type 1 infection in microglia cells.

Herpes simplex virus type 1 (HSV-1), a neurotropic DNA virus, establishes latency in neural tissues, with reactivation causing severe consequences like encephalitis. Emerging evidence links HSV-1 infection to chronic neuroinflammation and neurodegenerative diseases. Microglia, the central nervous system's (CNS) immune sentinels, express diverse receptors, including α7 nicotinic acetylcholine receptors (α7 nAChRs), critical for immune regulation. Recent studies suggest α7 nAChR activation protects against viral infections. Here, we show that α7 nAChR agonists, choline and PNU-282987, significantly inhibit HSV-1 replication in microglial BV2 cells. Notably, this inhibition is independent of the traditional ionotropic nAChR signaling pathway. mRNA profiling revealed that choline stimulates the expression of antiviral factors, IL-1ß and Nos2, and down-regulates the apoptosis genes and type A Lamins in BV2 cells. These findings suggest a novel mechanism by which microglial α7 nAChRs restrict viral infections by regulating innate immune responses.

Mirogabalin as a Therapeutic Option for Neuropathic Pain Emerging Post-endodontic Treatment: A Two-Case Report.

INTRODUCTION: Occlusal and percussion pain may manifest occasionally following endodontic treatment, influencing retreatment decisions. Two cases of periapical neuropathic pain, classified as post-traumatic trigeminal neuropathic pain according to the International Classification of Orofacial Pain, are presented. Although mirogabalin is effective in managing neuropathic pain, there is a lack of clinical reports on its use for occasional post-traumatic trigeminal neuropathic pain after endodontic treatment. These cases highlight clinical symptoms and successful treatment with mirogabalin for post-traumatic trigeminal neuropathic pain after endodontic treatment, providing clinicians a "take-away" lesson for improving patient condition. METHODS: The patients, referred by their primary dentist due to postendodontic abnormal pain, found no relief with antibiotics or nonsteroidal anti-inflammatory drugs. Although no findings including swelling or periapical radiolucency were observed around the tooth, they experienced occlusal and percussion pain. Local anesthetic testing showed that the pain originated from the peripheral area around the tooth rather than from central sensitization. Dental radiography and cone-beam computed tomography revealed no abnormal findings. Root canal retreatment was performed by a specialist in endodontic treatment. Although endodontic retreatment drastically decreased visual analog scale pain score, pain persisted. Based on the International Classification of Orofacial Pain criteria, diseases other than post-traumatic trigeminal neuropathic pain were excluded. Mirogabalin (10 mg/d) was prescribed once daily before bedtime. RESULTS: Visual analog scale scores gradually and drastically decreased 2 weeks after mirogabalin therapy. Several months later, no recurrence of postendodontic pain was observed after tapering off and discontinuing mirogabalin. CONCLUSIONS: These findings suggest the possibility of a new treatment method for post-traumatic trigeminal neuropathic pain after endodontic treatment.

Efficacy of Mirogabalin for Taxane-associated Chemotherapy-induced Peripheral Neuropathy in Perioperative Chemotherapy for Early Breast Cancer.

BACKGROUND/AIM: Treatment with taxanes can result in chemotherapy-induced peripheral neuropathy (CIPN). We investigated the efficacy and safety of mirogabalin for the treatment of CIPN in patients who had been administered perioperative chemotherapy including taxane-based agents for breast cancer. PATIENTS AND METHODS: We retrospectively analyzed the case of 43 patients with early breast cancer who received a taxane as perioperative chemotherapy and were administered mirogabalin at the diagnosis of CIPN. RESULTS: Thirty-six patients (83.7%) had grade 1 CIPN and the other seven patients (16.3%) had grade 2 CIPN. The median mirogabalin dose was 10 mg (5-30 mg). CIPN improved from grade 1 to 0 in 12 patients (27.9%) and from grade 2 to 1 in one patient (2.3%); 13 (30.2%) patients thus had an objective therapeutic response. There were no cases in which chemotherapy was reduced or discontinued due to CIPN. Adverse events were evaluated by Common Terminology Criteria for Adverse Events and included five cases of dizziness (11.7%), three of somnolence (7.0%), and two of nausea (4.7%), all of which were grade ≤2. There were no cases of serious (grade ≥3) adverse effects. CONCLUSION: Mirogabalin may be effective and safe for treating CIPN of patients who receive a taxane in a perioperative breast cancer setting.

Potential use of pinenes to improve localized insecticide injections targeting the western drywood termite (Blattodea: Kalotermitidae).

The western drywood termite, Incisitermes minor (Hagen), causes significant economic damage to wood structures in the United States of America, especially California. When infestation is not widespread, localized insecticide injections may be useful for remedial control. However, the extensive gallery structure of drywood termites and their tendency to aggregate at specific parts of the galleries can impact the efficacy of localized insecticide injection. Chemicals that attract termites from a distance may improve the localized insecticide injection by increasing the number of termites contacting the insecticide residues. Two volatile terpenes, α-pinene and ß-pinene, commonly found in many coniferous timber trees, were applied to artificial termite galleries to determine if termites were attracted from their original aggregation site. Furthermore, we examined if adding these pinenes would improve the overall efficacy of some insecticide products for drywood termite control. Behavioral assay results showed that the treatment with pinenes increased the likelihood that drywood termites would leave their original aggregation site and contact the treated part of the gallery. When tested with the pesticide products applied in a small area away from the termite aggregation, ß-pinene significantly accelerated the time course of mortality for the aqueous fipronil. The efficacy of disodium octaborate tetrahydrate dust was not influenced by the addition of pinenes. Implications for drywood termite management and future research directions are discussed.

Compound-Specific Isotope Analysis Provides Direct Evidence for Identifying the Source of Residual Pesticides Diazinon and Procymidone in the Soil-Plant System.

Compound-specific isotope analysis stands as a promising tool for unveiling the behavior of pesticides in agricultural environments. Using the commercial formulations of persistent fungicide procymidone (PRO) and less persistent insecticide diazinon (DIA), respectively, we analyzed the concentration and carbon isotope composition (δ13C) of the residual pesticides through soil incubation experiments in a greenhouse (for 150 days) and lab conditions (for 50-70 days). Our results showed that the magnitude of δ13C variation depends on pesticide specificity, in which PRO in the soil exhibited little variation in δ13C values over the entire incubation times, while DIA demonstrated an increased δ13C value, with the extent of δ13C variability affected by different spiking concentrations, plant presence, and light conditions. Moreover, the pesticides extracted from soils were isotopically overlapped with those from crop lettuce. Ultimately, the isotope composition of pesticides could infer the degradation and translocation processes and might contribute to identifying the source(s) of pesticide formulation in agricultural fields.

St. John's wort extract with a high hyperforin content does not induce P-glycoprotein activity at the human blood-brain barrier.

St. John's wort (SJW) extract, a herbal medicine with antidepressant effects, is a potent inducer of intestinal and/or hepatic cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp), which can cause clinically relevant drug interactions. It is currently not known whether SJW can also induce P-gp activity at the human blood-brain barrier (BBB), which may potentially lead to decreased brain exposure and efficacy of certain central nervous system (CNS)-targeted P-gp substrate drugs. In this study, we used a combination of positron emission tomography (PET) imaging and cocktail phenotyping to gain a comprehensive picture on the effect of SJW on central and peripheral P-gp and CYP activities. Before and after treatment of healthy volunteers (n = 10) with SJW extract with a high hyperforin content (3-6%) for 12-19 days (1800 mg/day), the activity of P-gp at the BBB was assessed by means of PET imaging with the P-gp substrate [11C]metoclopramide and the activity of peripheral P-gp and CYPs was assessed by administering a low-dose phenotyping cocktail (caffeine, omeprazole, dextromethorphan, and midazolam or fexofenadine). SJW significantly increased peripheral P-gp, CYP3A, and CYP2C19 activity. Conversely, no significant changes in the peripheral metabolism, brain distribution, and P-gp-mediated efflux of [11C]metoclopramide across the BBB were observed following the treatment with SJW extract. Our data suggest that SJW does not lead to significant P-gp induction at the human BBB despite its ability to induce peripheral P-gp and CYPs. Simultaneous intake of SJW with CNS-targeted P-gp substrate drugs is not expected to lead to P-gp-mediated drug interactions at the BBB.

Regiodivergent biosynthesis of bridged bicyclononanes.

Medicinal compounds from plants include bicyclo[3.3.1]nonane derivatives, the majority of which are polycyclic polyprenylated acylphloroglucinols (PPAPs). Prototype molecules are hyperforin, the antidepressant constituent of St. John's wort, and garcinol, a potential anticancer compound. Their complex structures have inspired innovative chemical syntheses, however, their biosynthesis in plants is still enigmatic. PPAPs are divided into two subclasses, named type A and B. Here we identify both types in Hypericum sampsonii plants and isolate two enzymes that regiodivergently convert a common precursor to pivotal type A and B products. Molecular modelling and substrate docking studies reveal inverted substrate binding modes in the two active site cavities. We identify amino acids that stabilize these alternative binding scenarios and use reciprocal mutagenesis to interconvert the enzymatic activities. Our studies elucidate the unique biochemistry that yields type A and B bicyclo[3.3.1]nonane cores in plants, thereby providing key building blocks for biotechnological efforts to sustainably produce these complex compounds for preclinical development.