Patent Application
20210163437
TRPV1 is a prominent signal integrator of the pain system, known to be activated by vanilloids, a family of endogenous and exogenous pain-evoking molecules, through the vanilloid-binding site (VBS). The extensive preclinical profiling of small molecule inhibitors provides intriguing evidence that TRPV1 inhibition can be a useful therapeutic approach. However, the dissimilarity of chemical species that activate TRPV1 creates a major obstacle to understanding the molecular mechanism of pain induction, which is viewed as a pivotal trait of the somatosensory system.
The Transient Receptor Potential Vanilloid-1 (TRPV1), also known as the “heat and capsaicin receptor”, is a prominent signal integrator of the somatosensory system.1,2 It is expressed primarily on pain fibers (Ad -and C-fibers) and has the unique ability to detect an array of noxious stimuli, including heat (≥42 ° C.), protons, polyunsaturated fatty acids (PUFAs), peptide toxins, and plant toxins. The TRPV1 expression pattern and its polymodality make it an intriguing target for pain treatment.
Vanilloids, both endogenous and exogenous, are pain-evoking molecules that activate TRPV1 through the vanilloid-binding site (VBS) located in the intracellular domain between the S3 and S4 transmembrane segments. This large and diverse family of TRPV1 ligands includes endovanilloids, such as the endocannabinoids anandamide, N-arachidonoyl dopamine (NADA), and lipoxygenase products of arachidonic acid. However, the most well-known and studied activators are the exo-vanilloid phytotoxins capsaicin and resiniferatoxin (RTX). The extensive preclinical profiling of small molecule TRPV1 inhibitors acting through the VBS provides intriguing evidence that TRPV1 inhibition can be a useful therapeutic approach for inflammatory, cancer, and neuropathic pain. Discerning the mechanism by which the TRPV1 VBS accommodates its abundance of diverse ligands would have important implications for future drug development efforts. A major obstacle to this endeavor is the inability to discern a lead motif within the diverse and chemically dissimilar range of known activating agents. Additionally, it is unclear which functional domains (out of the many characterized to date) are essential to elicit the desirable engagement with this receptor (i.e., activation/sensitization).
To get a further understanding the inventors have analyzed known agonists and antagonists (selective and non-selective, specific and non-specific, natural and synthetic compounds) of TRPV1 which were categorized into six distinctive families, each displaying unique chemical and functional characteristics.
Numerous structure-activity relationship (SAR) studies reveal three similar, yet distinct regions: 1) the vanilloid scaffold, 2) the carbonylic site (ester or amide), and 3) the lipophilic domain.
Previous studies have demonstrated that the vanilloid segment is important for the biological activity of agonists. In the absence of this unit, all the compounds studied were shown to be inactive. The carbonylic segment is integrated through a simple and inactivated ester or amide and is responsible for specific hydrogen bond interactions between the substrate and the receptor. The lipophilic aliphatic domain is another common region that is significantly different among agonists but is crucial for potency.
While examining the vast variety of TRPV1 antagonists, it was clear to the inventors that no common functional denominator (a requisite chemical/structural motif) can be identified among this spectrum of compounds. Some of the compounds slightly resemble one another, but others are completely unique (
To date, TRPV1 activation/inactivation through the VBS (either by agonists, or antagonists) has relied on the presence of these functional/structural domains. The majority of recent research efforts in this field have examined the interaction between an operational pharmacophore and the TRPV1-VBS binding site. However, conventional drug discovery efforts regard the presence of one of these groups as an indispensable requirement for any potential therapeutic agent/drug candidate.
The inventors have now shown the existence of a conceptually different family of TRPV1-activating agents acting through the VBS. This series of molecules contains none of the structural domains previously believed to be crucial for triggering the receptor-agent interactions. These compounds are highly compact, tricyclic, spherical spirolactones that share an angularly fused topology.
Here, we establish the existence of a unique synthetic agonists that interface with TRPV1 through the VBS, containing none of the molecular domains previously believed to be required for this interaction. The overarching value obtained from our inquiry is the novel advancement of the existing TRPV1 activation model. These findings uncover new potential in the area of pain treatment, providing a novel synthetic platform.
Thus, the present invention provides a compound of general formula (I):
Wherein R1 is selected from straight or branched C1-C10 alkyl, straight or branched C2-C10 alkenyl, straight or branched C2-C10 alkynyl; each optionally interrupted by at least one heteroatom and optionally substituted by at least one aryl group optionally substituted with at least one of —CN, —OH, alkoxy, amine, amide and halogen;
Rings A, B and C are each optionally a saturated or unsaturated ring having optionally at least one heteroatom; and are each optionally substituted by at least one group selected from straight or branched C1-C10 alkyl, straight or branched C2-C10 alkenyl, straight or branched C2-C10 alkynyl, CN, —OR4, —NR5R6, —C(═O)R7, halogen; each of said straight or branched C1-C10 alkyl, straight or branched C2-C10 alkenyl, straight or branched C2-C10 alkynyl are optionally substituted with at least one of —CN, —OH, alkoxy, amine, amide, halogen, aryl;
R4, R5, R6, R7 are each independently selected from H, halogen, —OH, —NH2, straight or branched C1-C10 alkyl, straight or branched C2-C10 alkenyl, straight or branched C2-C10 alkynyl, aryl, —O(C 1-C10)alkyl, NH2, amine; each of said straight or branched C1-C10 alkyl, straight or branched C2-C10 alkenyl, straight or branched C2-C10 alkynyl are optionally substituted with at least one of —CN, —OH, alkoxy, amine, amide, halogen, aryl;
n is an integer selected from 1-10; —C(n)— is selected from a straight or branched alkylene, straight or branched alkenylene, straight or branched alkynylene; optionally interrupted by at least one heteroatom;
m is an integer selected from 1-10; —C(m)— is selected from a straight or branched alkylene, straight or branched alkenylene, straight or branched alkynylene; optionally interrupted by at least one heteroatom;
l is an integer selected from 1-10; —C(l)— is selected from a straight or branched alkylene, straight or branched alkenylene, straight or branched alkynylene; optionally interrupted by at least one heteroatom.
In another one of its aspects, the invention provides a compound of general formula (II):
Wherein R1 is selected from straight or branched C1-C10 alkyl, straight or branched C2-C10 alkenyl, straight or branched C2-C10 alkynyl; each optionally interrupted by at least one heteroatom and optionally substituted by at least one aryl group optionally substituted with at least one of —CN, —OH, alkoxy, amine, amide, halogen;
Rings A, B and C are each optionally a saturated or unsaturated ring having optionally at least one heteroatom; and are each optionally substituted by at least one group selected from straight or branched C1-C10 alkyl, straight or branched C2-C10 alkenyl, straight or branched C2-C10 alkynyl, CN, —OR4, —NR5R6, —C(═O)R7, halogen; each of said straight or branched C1-C10 alkyl, straight or branched C2-C10 alkenyl, straight or branched C2-C10 alkynyl are optionally substituted with at least one of —CN, —OH, alkoxy, amine, amide, halogen, aryl;
R4, R5, R6, R7 are each independently selected from H, halogen, —OH, —NH2, straight or branched C1-C10 alkyl, straight or branched C2-C10 alkenyl, straight or branched C2-C10 alkynyl, aryl, —O(C1-C10)alkyl, NH2, amine; each of said straight or branched C1-C10 alkyl, straight or branched C2-C10 alkenyl, straight or branched C2-C10 alkynyl are optionally substituted with at least one of —CN, —OH, alkoxy, amine, amide, halogen, aryl;
n is an integer selected from 1-10; —C(n)— is selected from a straight or branched alkylene, straight or branched alkenylene, straight or branched alkynylene; optionally interrupted by at least one heteroatom;
m is an integer selected from 1-10; —C(m)— is selected from a straight or branched alkylene, straight or branched alkenylene, straight or branched alkynylene; optionally interrupted by at least one heteroatom;
l is an integer selected from 1-10; —C(l)— is selected from a straight or branched alkylene, straight or branched alkenylene, straight or branched alkynylene; optionally interrupted by at least one heteroatom.
In some embodiments, R1 is straight or branched C1-C10 alkyl. In some embodiments, R1 is straight or branched C2-C10 alkenyl. In other embodiments, R1 is selected from straight or branched C1-C10 alkyl, straight or branched C2-C10 alkenyl that is interrupted by at least one heteroatom. In further embodiments, R1 is selected from straight or branched C1-C10 alkyl, straight or branched C2-C10 alkenyl substituted by at least one phenyl optionally substituted with at least one of —CN, —OH, alkoxy, amine, amide and halogen. In other embodiments, R1 is selected from straight or branched C1-C10 alkyl, straight or branched C2-C10 alkenyl substituted by at least one phenyl substituted with at least one of —CN, —OH, alkoxy, amine, amide and halogen.
In some embodiments, wherein Ring C is a saturated ring. In other embodiments, Ring C is a saturated ring substituted by at least one group selected from straight or branched C1-C10 alkyl, straight or branched C2-C10 alkenyl, straight or branched C2-C10 alkynyl, CN, —OR4, —NR5R6, —C(═O)R7, halogen; each of said straight or branched C1-C10 alkyl, straight or branched C2-C10 alkenyl, straight or branched C2-C10 alkynyl are optionally substituted with at least one of —CN, —OH, alkoxy, amine, amide, halogen, aryl.
In further embodiments, Ring C is an unsaturated ring. In other embodiments, Ring C is an unsaturated ring substituted by at least one group selected from straight or branched C1-C10 alkyl, straight or branched C2-C10 alkenyl, straight or branched C2-C10 alkynyl, CN, —OR4, —NR5R6, —C(═O)R7, halogen; each of said straight or branched C1-C10 alkyl, straight or branched C2-C10 alkenyl, straight or branched C2-C10 alkynyl are optionally substituted with at least one of —CN, —OH, alkoxy, amine, amide, halogen, aryl.
In some embodiments, m=1, —C(m)- being a C1-alkylene optionally interrupted by at least one heteroatom. In some embodiments, n=1, —C(n)- being C1-alkylene, optionally interrupted by at least one heteroatom. In further embodiments, n=2, —C(n)- being C2-alkylene, optionally interrupted by at least one heteroatom. In other embodiments, n=3, —C(n)- being C3-alkylene, optionally interrupted by at least one heteroatom. In further embodiments, l=1, —C(l)- is a C1-alkylene, optionally interrupted by at least one heteroatom. In further embodiments, l=2, —C(l)- is a C2-alkenylene, optionally interrupted by at least one heteroatom.
In some embodiments, a compound of the invention is selected from:
The invention further provides a pharmaceutical composition comprising at least one compound as defined hereinabove and below.
In another aspect, the invention provides a compound as defined herein above and below for use in the treatment of pain, including any condition or disorder associated therewith.
In another aspect, the invention provides a compound as defined herein above and below for use in the management of pain, including any condition or disorder associated therewith.
The invention provides a method of treating or managing pain and pain related disorders and symptoms in a subject in need thereof, said method comprising administering to a patient a composition as defined herein above and below.
The term “straight or branched C1-C10 alkyl” refers to a saturated hydrocarbon chain having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and the corresponding hydrogen atoms.
The term “straight or branched C2-C10 alkenyl” refers to an unsaturated hydrocarbon chain having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and the corresponding hydrogen atoms and at least one double bond at any position in the chain.
The term “straight or branched C2-C10 alkynyl” refers to an unsaturated hydrocarbon chain having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and the corresponding hydrogen atoms and at least one triple bond at any position in the chain.
The term aryl refers to an aromatic hydrocarbon single ring or fused ring system having between 6 to 18 carbon atoms. This term may also include a heteroaryl ring having at least one heteroatom.
The term “alkoxy” refers to a —OR radical wherein R is selected from a straight or branched C1-C10 alkyl, straight or branched C2-C10 alkenyl, straight or branched C2-C10 alkenyl.
The term “amine” refers to a —NRR′R″ radical wherein each of R, R′, R″ is independently selected from H, a straight or branched C1-C10 alkyl, straight or branched C2-C10 alkenyl, straight or branched C2-C10 alkenyl.
The term “amide” refers to a —C(═O)NRR′R″ radical wherein each of R, R′, R″ is independently selected from H, a straight or branched C1-C10 alkyl, straight or branched C2-C10 alkenyl, straight or branched C2-C10 alkenyl.
The term “halogen” refers to any one of F, Cl, Br, I.
The term “heteroatom” refers to any one of O, S, P, N.
When referring to Rings A, B and C being saturated, this should be understood to refer to said ring, independently, having only sigma bonds between the atoms forming the ring. When referring to Rings A, B and C being unsaturated, this should be understood to refer to said ring, independently, having at least one unsaturated bond (double and/or triple) at any position in the ring between the atoms forming the ring.
In some embodiments Ring A is a saturated 5, 6, 7, or 8 member ring (thus the ring consists of 5, 6, 7 or 8 atoms connected to each other with saturated single bonds only). In other embodiments, Ring A is an unsaturated 5, 6, 7 or 8 member ring (thus the ring comprises at least one unsaturated bond within the ring structure. Said unsaturated bond can be a double and/or a triple bond between any two atoms in the ring). In further embodiments Ring A is a 5-7 member ring having at least one heteroatom (thus said ring comprises at least one atom that is different than carbon being selected from O, N or S at any position in the ring. When valency permits heteroatom is substituted with one or more H, straight or branched C1-C10 alkyl, straight or branched C2-C10 alkenyl, straight or branched C2-C10 alkynyl.
The term “—C(n)—” as used herein refers to a straight or branched hydrocarbon chain that can be saturated (i.e. having only single bonds connecting the atoms in the chain) or unsaturated (i.e. having at least one unsaturated bond, double or triple bond, connecting the atoms in the ring), having m carbon atoms. “—C(n)—” chain can be optionally interrupted by at least one heteroatom, thus any two carbon atoms in the chain can be interrupted with at least one heteroatom between them (for example . . . —C—N—C— . . . ). Said heteroatom selected from O, N, S, P, when valency permits heteroatom is substituted with one or more H, straight or branched C1-C10 alkyl, straight or branched C2-C10 alkenyl, straight or branched C2-C10 alkynyl.
The term “—C(m)—” as used herein refers to a straight or branched hydrocarbon chain that can be saturated (i.e. having only single bonds connecting the atoms in the chain) or unsaturated (i.e. having at least one unsaturated bond, double or triple bond, connecting the atoms in the ring), having m carbon atoms. “—C(m)—” chain can be optionally interrupted by at least one heteroatom, thus any two carbon atoms in the chain can be interrupted with at least one heteroatom between them (for example . . . —C—N—C— . . . ). Said heteroatom selected from O, N, S, P, when valency permits heteroatom is substituted with one or more H, straight or branched C1-C10 alkyl, straight or branched C2-C10 alkenyl, straight or branched C2-C10 alkynyl.
In some embodiments, —C(m)— is selected from a C1-C10 straight or branched alkylene, C2-C10 straight or branched alkenylene, C2-C10 straight or branched alkynylene. In some further embodiments, —C(m)— is a C1-C10 straight or branched alkylene.
The compounds of the present application may include one or more asymmetric chiral center. Thus, the disclosure of the present application relates to any stereoisomer of the compound as it may occur. The chiral/assymetric centers are designated by the symbols “R” or “S,” depending on the configuration of substituents around the chiral carbon atom. It should be understood that the invention encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric, and epimeric forms, as well as d-isomers and 1-isomers, and mixtures thereof. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art. Additionally, the compounds disclosed herein may exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. Additionally, compounds may exist as tautomers; all tautomeric isomers are provided by this invention. Additionally, the compounds disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms.
The term “pain” as used herein should be understood to relate to any type of pain of any magnitude or duration, caused by any means (internal or external to the human body of a subject treated with a composition of the invention). For example, said pain may be caused by a bodily system whose dysfunction may be causing the pain (e.g., nervous, gastrointestinal). Said pain can be chronic pain or single episode pain, having any duration or pattern of occurrence. Said pain may be localized either in a single or multiple region of the body. Said pain may be of any intensity and time since onset. The pain treated by a composition or compound of the invention may be selected from at least one of the following classifications: nociceptive pain, inflammatory pain (typically associated with tissue damage and the infiltration of immune cells), pathological pain (typically associated with a disease state caused by damage to the nervous system or by its abnormal function such as fibromyalgia, irritable bowel syndrome, tension type headache, etc.).
The term “treatment of pain” as used herein refers to the administering of a therapeutic amount of a composition of the present invention comprising a compound of the present invention, which is effective to reduce, prevent or ameliorate pain of any magnitude felt by a subject including any undesired symptoms associated with the sensation of pain caused by any means (internal or external to the human body of a subject in need thereof).
The term “management of pain” as used herein refers to the administering of a therapeutic amount of a composition of the present invention comprising a compound of the present invention, which is effective to allow a subject suffering from any type or magnitude of pain, including any disorders or symptoms associated therewith, to control and ease the suffering and improve the quality of life of said subject, suffering from pain (including chronic pain).
The “effective amount” for purposes disclosed herein is determined by such considerations as may be known in the art. The amount must be effective to achieve the desired therapeutic effect as described above, depending, inter alia, on the type and severity of the disease to be treated and the treatment regime. The effective amount is typically determined in appropriately designed clinical trials (dose range studies) and the person versed in the art will know how to properly conduct such trials in order to determine the effective amount. As generally known, an effective amount depends on a variety of factors including the affinity of the ligand to the receptor, its distribution profile within the body, a variety of pharmacological parameters such as half-life in the body, on undesired side effects, if any, on factors such as age and gender, etc.
The pharmaceutical compositions of the invention may comprise additionally any other suitable substances such as other therapeutically useful substances, diagnostically useful substances, pharmaceutically acceptable carriers or the like.
When referring to “composition(s)” or “pharmaceutical composition(s)” the present invention seeks to include any compositions suitable for oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration or administration via an implant. The compositions may be prepared by any method well known in the art of pharmacy.
Such methods include the step of bringing in association compounds used in the invention or combinations thereof with any auxiliary agent. The auxiliary agent(s), also named accessory ingredient(s), include those conventional in the art, such as carriers, fillers, binders, diluents, disintegrants, lubricants, colorants, flavouring agents, anti-oxidants, and wetting agents. Pharmaceutical compositions suitable for oral administration may be presented as discrete dosage units such as pills, tablets, drag-es or capsules, or as a powder or granules, or as a solution or suspension. The active ingredient may also be presented as a bolus or paste. The compositions can further be processed into a suppository or enema for rectal administration. The invention further includes a pharmaceutical composition, as hereinbefore described, in combination with packaging material, including instructions for the use of the composition for a use as hereinbefore described. For parenteral administration, suitable compositions include aqueous and non-aqueous sterile injection. The compositions may be presented in unit-dose or multi-dose containers, for example sealed vials and ampoules, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of sterile liquid carrier, for example water, prior to use. For transdermal administration, e.g. gels, patches or sprays can be contemplated. Compositions or formulations suitable for pulmonary administration e.g. by nasal inhalation include fine dusts or mists which may be generated by means of metered dose pressurized aerosols, nebulisers or insufflators.
The exact dose and regimen of administration of the composition will necessarily be dependent upon the therapeutic or nutritional effect to be achieved and may vary with the particular formula, the route of administration, and the age and condition of the individual subject to whom the composition is to be administered.
It must be noted that, as used in this specification and the appended claims, the singular forms “a”, “an” and “the” include plural referents unless the content clearly dictates otherwise.
Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any integer or step or group of integers and steps.
The subject matter regarded as the invention is particularly pointed out and distinctly claimed in the concluding portion of the specification. The invention, however, both as to organization and method of operation, together with objects, features, and advantages thereof, may best be understood by reference to the following detailed description when read with the accompanying drawings in which:
It will be appreciated that for simplicity and clarity of illustration, elements shown in the figures have not necessarily been drawn to scale. For example, the dimensions of some of the elements may be exaggerated relative to other elements for clarity. Further, where considered appropriate, reference numerals may be repeated among the figures to indicate corresponding or analogous elements.
In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, it will be understood by those skilled in the art that the present invention may be practiced without these specific details. In other instances, well-known methods, procedures, and components have not been described in detail so as not to obscure the present invention.
Tricyclic spirolactones are frequently observed as scaffold segments of various natural biochemical compounds. Examples of these structures have been identified in carbohydrates, terpenoids, antibiotics, and many other compounds. Recently, we reported general and collective syntheses of phylogenetically different tricyclic, angularly fused spirolactones via controlled cyclizations of easily accessible common cycloalkylmethylene key precursors (
Tricyclic spirolactones activate TRPV1 through the VBS domain. Following the established protocol, we prepared a series of angularly fused lactones featuring various tricyclic topologies (displaying varying ring sizes and fusion combinations) and diverse electronic and steric characteristics (
To examine whether the compact tricyclic spirolactones activate TRPV1, we scanned a library of synthesized compounds illustrated in
TRPV1 activation by tricyclic spirolactones depends on their saturation and the functionality state. After concluding that unsaturated structures can activate the TRPV1 via the VBS, we were compelled to examine the functionality of fully saturated variants (i.e., the same range of molecules without alkenes, as shown in
We were intrigued by the possibility of applying the established protocol to other spirolactones. We thus prepared a range of tricyclic scaffolds sharing various topologies and functional groups integrated within the scaffold, as shown in
This observation strengthens our hypothesis that an alkene element is indispensable for initiating the substrate-receptor interaction. However, for compounds 24-26, which resemble the topology of compounds 10 and 15 (active compounds, see
Integration of the aromatic anchor across the active scaffolds. Previous studies have clearly indicated the importance of the aromatic domains in TRPV1 activation through the VBS. Thus, we postulated that the introduction of aromatic domains would provide additional tools to manipulate and better understand our system. To test the changes in the intensity of binding (receptor-ligand interaction), the leading topologically diverse scaffolds of compounds 10, 12, and 13 (
To examine their activation profile, the prepared compounds (
Tricyclic spirolactones evoke robust channel activation. TRPV1 is a non-selective cationic ion channel with a typical current profile. To examine whether our novel structure architecture activates the channel similarly as other VBS -associated agonists, we analyzed the current profile using the whole-cell configuration of the patch clamp technique. Using voltage ramps between −80 and +80 mV, we analyzed the channel response to 32 and capsaicin. As shown in
To further analyze the role of the aromatic anchor in TRPV1 activation by spirolactones, we compared the affinity of 13 to its vanilloid derivative 32. As clearly showed in
Thus, like other vanilloids, our novel scaffold can robustly activate TRPV1 through the VBS. On the basis of the obtained results, we were intrigued to examine the behavior of fully saturated spirolactones that were incorporated with aromatic modules. Taking into account the fact that TRPV1 activation by tricyclic spirolactones depends on their saturation, we were interested if such structural modification (compensation of the alkene group with aromatic moiety) could cause the activation of the receptor.
To test this assumption, we conducted an experiment in which compound 18 (saturated analogue of active 13;
In conclusion, the overarching value obtained from our inquiry is the ability to advance the existing TRPV1 activation model, which is supported by over two decades of dedicated research. Three molecular pharmacophores/domains/functional groups—the vanilloid, benzene, or other aromatic heterocycle; the lipophilic hydrocarbon chain; and the linearly fused terpenoid moiety—have been thought indispensable for an agonist/antagonist to trigger receptor-agent interactions through the VBS. This understanding was achieved because the interactive potency of the residual structure is either lost or significantly diminished when these key elements are removed. Herein, we establish the existence of a conceptually unique family of activating agents that interface with the TRPV1 receptor through the VBS. The reported series of molecules-highly compact, tricyclic, spherical spirolactones-contain none of the structural domains previously believed to be integral for receptor interaction.
When these lactones were anchored with an aromatic residue, the efficacy of the compound increased. However, based on our observations, the nature of the aromatic anchor is inconsequential; similar efficacy was detected for the basic benzylic-enriched scaffolds and their vanilloid alternatives. As previously demonstrated,8,14-18 the aromatic interaction between agonist and the tyrosine residue in the VBS augments the TRPV1 response. This analysis led to the assumption that this interaction is not required for the binding to result in TRPV1 activation. Here, we show that TRPV1 activation through the VBS does not depend on the aromatic interaction. As evidenced by the robust response of compound 13 compared to other spirolactones, we believe that other yet-to-be-determined interactions are necessary for the activation of TRPV1 by hydrophobic molecules. The addition of an aromatic moiety to compound 13 created compounds (31 and 32) with capsaicin-like activity. Thus, our compounds reveal the flexibility of the VBS.
Further structural analysis is required to understand the interactions that control the activation of TRPV1 through this binding pocket.
We humbly hope that our findings uncover new potential in the area of pain treatment, providing a novel synthetic platform for further research. Our synthetic strategy is short, regioselective, and offers the possibility to access a broad spectrum of quaternary carbon-centered spiranoid scaffolds.
While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those of ordinary skill in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/IL2018/050546 | 5/17/2018 | WO | 00 |
| Number | Date | Country | |
|---|---|---|---|
| 62507394 | May 2017 | US |
