A good post copied from IHUB,
Fletch
sokol Member Level Wednesday, 10/20/21 10:34:47 AM
Re: None 0
Post # of 333358
The drug Anavex 2-73 (Blarcamesine) seems to be very different from other drugs classified as Sigma 1 agonist. Anavex 2-73 is multi-targeted directed ligand (MTDL) approach, with one molecule that exerts poly-pharmacological actions. It may be a winning strategy that overcomes the pharmacokinetic issues linked to the administration of diverse drugs. Blarcamesine can activate both M1 and s1 receptors with high potency and selectivity. It may not only be active itself, but it may be active as a pro-drug. AVXL 2-73's metabolite is 19-144, which may protect against amyloid and oxidative stress. Reportedly, the metabolite, 19-144, may offer a longer duration of action. A theory is that cholinomimetic-only compounds may not have as much benefit as the mixed mechanism - a mixed ligand such as AVXL 2-73. See the three articles below.
1. Multi-Target Directed Ligands (MTDLs) Binding the s1 Receptor as Promising Therapeutics: State of the Art and Perspectives
The sigma-1 (s1) receptor is a ‘pluripotent chaperone’ protein mainly expressed at the mitochondria–endoplasmic reticulum membrane interfaces where it interacts with several client proteins. This feature renders the s1 receptor an ideal target for the development of multifunctional ligands, whose benefits are now recognized because several pathologies are multifactorial. Indeed, the current therapeutic regimens are based on the administration of different classes of drugs in order to counteract the diverse unbalanced physiological pathways associated with the pathology. Thus, the multi-targeted directed ligand (MTDL) approach, with one molecule that exerts poly-pharmacological actions, may be a winning strategy that overcomes the pharmacokinetic issues linked to the administration of diverse drugs. This review aims to point out the progress in the development of MTDLs directed toward s1 receptors for the treatment of central nervous system (CNS) and cancer diseases, with a focus on the perspectives that are proper for this strategy. The evidence that some drugs in clinical use unintentionally bind the s1 protein (as off-target) provides a proof of concept of the potential of this strategy, and it strongly supports the promise that the s1 receptor holds as a target to be hit in the context of MTDLs for the therapy of multifactorial pathologies.
...The most exploited paradigm in medicinal chemistry is the “one-target, one-disease”, according to which ligands are developed to act toward a single target in order to exert a beneficial effect. This kind of approach, even if largely applied, may lead to unsuccessful results. Indeed, pathologies are mostly based on tangled mechanisms that involve different kinds of targets. Thus, a single target approach could be inappropriate because of its impossibility to produce an effect on the different pathways associated with the pathology.
On the basis of this idea, a multi-target strategy has been proposed in order to hit at the same time the diverse targets involved and modulate the diverse mechanisms that underlie the pathology......
The first step of this multi-target strategy has been the co-administration of more drugs all together, with the aim of obtaining a synergic effect.....
MTDLs Acting at s1 Receptor and Cholinergic System
Drug metabolism leads to metabolites that can be more potent or less potent than the parent drug. In the former case, the drug can be considered a sort of prodrug. Thus, the simultaneous presence of the two chemical entities may produce a synergistic powerful effect....
...Many pharmacological and genetic data have proven that activation of muscarinic M1 receptors (mAChRs) attenuates symptoms of neurodegenerative pathologies [78,79], as in the case of MTDLs able to bind both M1 and s1 receptors. The most investigated compound representative of this class is ANAVEX 2-73 (also known as Blarcamesine) (Figure 2). This compound is in advanced clinical phases for several CNS diseases such as AD, Parkinson’s disease (PD), Rett, and Fragile X Syndromes (anavex.com/#!/pipeline, accessed Apr 3, 2021). In addition to binding M1 and s1 receptors, Blarcamesine also binds M2–M4 receptors (with micromolar affinity), Na+ channel site 2, and NMDA receptor (NMDAR) [80,81]. In this context, Fisher and co-workers, who previously developed orthosteric M1 receptors agonists (e.g., AF102B, AF267B, and AF292), extended their approach in order to target also s1 receptors. With this aim, compound AF710B (also known as ANAVEX 3-71, Figure 2) that can activate both M1 and s1 receptors with high potency and selectivity was identified [66]. AF710B is a positive allosteric modulator (PAM) of M1 receptor, as it improves the efficacy of carbachol, and this activity, together with a comparable agonism at the s1 receptor can preserve synaptic elements in vitro. In vivo studies performed on trihexyphenidyl-treated rats and 3xTg-AD mice showed that AF710B can restore cognitive deficits and attenuate signs of AD phenotypes by the reduction of ß-secretase 1 (BACE1) levels, GSK3ß and CDK5/p25 activity (which contribute to the hyperphosphorylation of tau protein), neuroinflammation, soluble and insoluble Aß40 and Aß42 plaques, and tau pathology [82]. In fact, AF710B reduces the expression of the putative BACE1, so that proteolytic fragments produced by ß-secretase were considerably lower in 3xTg-AD treated than in untreated mice. Moreover, tau kinases GSK3ß and CDK5 take part in the mechanism of hyperphosphorylation of tau protein. In particular, in AD patients, CDK5 activator p35 is cleaved to produce the protein p25, which binds with high affinity and activates GSK3ß [83]. The activation of M1 receptors produces a reduction of GSK3ß expression, while the activation of s1 prevents the formation of CDK5/p25. Therefore, the inhibition of GSK3ß and CDK/p25 by AF710B, upon interaction with both M1 and s1 receptors, results as a promising approach in the treatment of tauopathies [82]....
...The effect of s1 receptors in inflammation through microglia modulation has been reported [54,86,87], and AF710B was shown to reduce reactive astrocytes and activated microglia in the animals, as detected by the low levels of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (Iba-1). Notably, astrocytes and microglia are increased in number and size in AD patients.
Another study performed using AF710B on McGill-R-Thyl-APP transgenic (tg) rats revealed that this MTDL can reduce amyloid pathology and markers of neuroinflammation while increasing amyloid cerebrospinal fluid clearance and synaptic marker. The most important achievement is represented by the prolonged duration of these effects, which are maintained five weeks after the treatment is interrupted [88].
In addition to AF710B and ANAVEX 2-73, Anavex Life Sciences Corp portfolio comprehends an isomer of ANAVEX 2-73, named ANAVEX 1-41 (Figure 2) that next to the activity toward s1 and M1 receptors, also displays activity for a1, 5-HT2, and D3 receptors [81], with an indication for the treatment of depression, stroke, and neurodegenerative diseases (anavex.com/#!/pipeline)....
Conclusions and Perspectives
This review aims to point out the state of the art of MTDLs interacting with the s1 receptor. As a result of its pluripotent chaperone activity, the s1 receptor has the potential to interact and modulate several targets involved in a number of diseases and syndromes. The evidence that several compounds already in clinical use (e.g., Donepezil, HP, etc.) unintentionally bind the s1 receptor has shed light on the already exploited interaction with this protein as a successful strategy in treating illnesses or associated symptoms through a MTDLs approach. Donepezil, whose interaction with s1 receptors in vivo has been ascertained by receptor occupancy studies in the human brain [94,158], is co-administered together with Memantine through prescription medicines (i.e., Namzaric). On this basis, the rational development of MTDLs with a s1 intentional targeting profile may lead to more important therapeutic actions. The amount of herein listed proteins, which are the object of the MTLDs development in association with the s1 receptor, is not intended to be exhaustive. Other proteins may be taken into consideration in the MTDLs development, considering the wide range of s1 receptor direct and indirect interactors. Cannabinoid type-2 (CB2) receptors are an example, with recent support from computational methods that point out a partial overlap of the s1 and CB2 receptors’ pharmacophores [159]. These data strongly suggest the adoption of a merging approach for the development of dual s1/CB2 receptors ligands for a synergistic exploitation of the pathways activated by the two targets in oncology and neurodegenerative diseases. A number of s ligands, besides interacting at the two subtypes (see Section 3.7), are able to modulate the efflux pump P-glycoprotein (P-gp) [150,160]. This double action is worthy of being more intentionally addressed, as it may serve as a strategy to face drug-resistant tumors: the compound overcomes P-gp, which is overexpressed in many resistant tumors and exerts its cytotoxic activity (as a s1 antagonist). Importantly, this same double action may also have a role in the treatment of CNS diseases through the bypass of the P-gp at the BBB. The waving interest in s receptors research increased during the COVD-19 pandemic, when the proteins were found as important key host dependency factors for coronavirus infections. However, while the exploitability of the s1 receptor as a druggable target against coronavirus still needs to be fully investigated and validated, it appears clear that this protein is involved in a plethora of pathways hampered in multifactorial CNS and cancer diseases, rendering the s1 receptor a full-fledged target for the development of multifunctional therapeutics.
https://www.mdpi.com/1422-0067/22/12/6359/htm
2. See also: Anavex Life Sciences Corp. Presents Data on Neuroprotective Evidence for ANAVEX 2-73, Lead Compound for Alzheimer's Disease
...ANAVEX 2-73 is not only active in and of itself, but is also a pro-drug. Its only metabolite, ANAVEX 19-144, is also active (in animal models)....
...ANAVEX 19-144, when administered prior to amyloid 25-35, protects against amyloid 25-35-induced amnesia in mice.
- ANAVEX 19-144 protects against amyloid 25-35-induced oxidative stress, measured by lipid peroxidation in hippocampal cells.
“It is hypothesized that cholinomimetic-only compounds would not have as much benefit as the mixed mechanism of the aminotetrahydrofurans, which may be potentiating. Interestingly, the pro drug and active drug effect of ANAVEX 2-73, which has ANAVEX 19-144 ‘embedded’ in it, may offer a longer duration of action,” said Dr. Tangui Maurice, PhD.....
https://www.biospace.com/article/releases/ana...se-405521/
3. Blarcamesine
It is a mixed ligand for sigma1/muscarinic receptors.
https://www.alzforum.org/therapeutics/blarcamesine
Fletch
sokol Member Level Wednesday, 10/20/21 10:34:47 AM
Re: None 0
Post # of 333358
The drug Anavex 2-73 (Blarcamesine) seems to be very different from other drugs classified as Sigma 1 agonist. Anavex 2-73 is multi-targeted directed ligand (MTDL) approach, with one molecule that exerts poly-pharmacological actions. It may be a winning strategy that overcomes the pharmacokinetic issues linked to the administration of diverse drugs. Blarcamesine can activate both M1 and s1 receptors with high potency and selectivity. It may not only be active itself, but it may be active as a pro-drug. AVXL 2-73's metabolite is 19-144, which may protect against amyloid and oxidative stress. Reportedly, the metabolite, 19-144, may offer a longer duration of action. A theory is that cholinomimetic-only compounds may not have as much benefit as the mixed mechanism - a mixed ligand such as AVXL 2-73. See the three articles below.
1. Multi-Target Directed Ligands (MTDLs) Binding the s1 Receptor as Promising Therapeutics: State of the Art and Perspectives
The sigma-1 (s1) receptor is a ‘pluripotent chaperone’ protein mainly expressed at the mitochondria–endoplasmic reticulum membrane interfaces where it interacts with several client proteins. This feature renders the s1 receptor an ideal target for the development of multifunctional ligands, whose benefits are now recognized because several pathologies are multifactorial. Indeed, the current therapeutic regimens are based on the administration of different classes of drugs in order to counteract the diverse unbalanced physiological pathways associated with the pathology. Thus, the multi-targeted directed ligand (MTDL) approach, with one molecule that exerts poly-pharmacological actions, may be a winning strategy that overcomes the pharmacokinetic issues linked to the administration of diverse drugs. This review aims to point out the progress in the development of MTDLs directed toward s1 receptors for the treatment of central nervous system (CNS) and cancer diseases, with a focus on the perspectives that are proper for this strategy. The evidence that some drugs in clinical use unintentionally bind the s1 protein (as off-target) provides a proof of concept of the potential of this strategy, and it strongly supports the promise that the s1 receptor holds as a target to be hit in the context of MTDLs for the therapy of multifactorial pathologies.
...The most exploited paradigm in medicinal chemistry is the “one-target, one-disease”, according to which ligands are developed to act toward a single target in order to exert a beneficial effect. This kind of approach, even if largely applied, may lead to unsuccessful results. Indeed, pathologies are mostly based on tangled mechanisms that involve different kinds of targets. Thus, a single target approach could be inappropriate because of its impossibility to produce an effect on the different pathways associated with the pathology.
On the basis of this idea, a multi-target strategy has been proposed in order to hit at the same time the diverse targets involved and modulate the diverse mechanisms that underlie the pathology......
The first step of this multi-target strategy has been the co-administration of more drugs all together, with the aim of obtaining a synergic effect.....
MTDLs Acting at s1 Receptor and Cholinergic System
Drug metabolism leads to metabolites that can be more potent or less potent than the parent drug. In the former case, the drug can be considered a sort of prodrug. Thus, the simultaneous presence of the two chemical entities may produce a synergistic powerful effect....
...Many pharmacological and genetic data have proven that activation of muscarinic M1 receptors (mAChRs) attenuates symptoms of neurodegenerative pathologies [78,79], as in the case of MTDLs able to bind both M1 and s1 receptors. The most investigated compound representative of this class is ANAVEX 2-73 (also known as Blarcamesine) (Figure 2). This compound is in advanced clinical phases for several CNS diseases such as AD, Parkinson’s disease (PD), Rett, and Fragile X Syndromes (anavex.com/#!/pipeline, accessed Apr 3, 2021). In addition to binding M1 and s1 receptors, Blarcamesine also binds M2–M4 receptors (with micromolar affinity), Na+ channel site 2, and NMDA receptor (NMDAR) [80,81]. In this context, Fisher and co-workers, who previously developed orthosteric M1 receptors agonists (e.g., AF102B, AF267B, and AF292), extended their approach in order to target also s1 receptors. With this aim, compound AF710B (also known as ANAVEX 3-71, Figure 2) that can activate both M1 and s1 receptors with high potency and selectivity was identified [66]. AF710B is a positive allosteric modulator (PAM) of M1 receptor, as it improves the efficacy of carbachol, and this activity, together with a comparable agonism at the s1 receptor can preserve synaptic elements in vitro. In vivo studies performed on trihexyphenidyl-treated rats and 3xTg-AD mice showed that AF710B can restore cognitive deficits and attenuate signs of AD phenotypes by the reduction of ß-secretase 1 (BACE1) levels, GSK3ß and CDK5/p25 activity (which contribute to the hyperphosphorylation of tau protein), neuroinflammation, soluble and insoluble Aß40 and Aß42 plaques, and tau pathology [82]. In fact, AF710B reduces the expression of the putative BACE1, so that proteolytic fragments produced by ß-secretase were considerably lower in 3xTg-AD treated than in untreated mice. Moreover, tau kinases GSK3ß and CDK5 take part in the mechanism of hyperphosphorylation of tau protein. In particular, in AD patients, CDK5 activator p35 is cleaved to produce the protein p25, which binds with high affinity and activates GSK3ß [83]. The activation of M1 receptors produces a reduction of GSK3ß expression, while the activation of s1 prevents the formation of CDK5/p25. Therefore, the inhibition of GSK3ß and CDK/p25 by AF710B, upon interaction with both M1 and s1 receptors, results as a promising approach in the treatment of tauopathies [82]....
...The effect of s1 receptors in inflammation through microglia modulation has been reported [54,86,87], and AF710B was shown to reduce reactive astrocytes and activated microglia in the animals, as detected by the low levels of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (Iba-1). Notably, astrocytes and microglia are increased in number and size in AD patients.
Another study performed using AF710B on McGill-R-Thyl-APP transgenic (tg) rats revealed that this MTDL can reduce amyloid pathology and markers of neuroinflammation while increasing amyloid cerebrospinal fluid clearance and synaptic marker. The most important achievement is represented by the prolonged duration of these effects, which are maintained five weeks after the treatment is interrupted [88].
In addition to AF710B and ANAVEX 2-73, Anavex Life Sciences Corp portfolio comprehends an isomer of ANAVEX 2-73, named ANAVEX 1-41 (Figure 2) that next to the activity toward s1 and M1 receptors, also displays activity for a1, 5-HT2, and D3 receptors [81], with an indication for the treatment of depression, stroke, and neurodegenerative diseases (anavex.com/#!/pipeline)....
Conclusions and Perspectives
This review aims to point out the state of the art of MTDLs interacting with the s1 receptor. As a result of its pluripotent chaperone activity, the s1 receptor has the potential to interact and modulate several targets involved in a number of diseases and syndromes. The evidence that several compounds already in clinical use (e.g., Donepezil, HP, etc.) unintentionally bind the s1 receptor has shed light on the already exploited interaction with this protein as a successful strategy in treating illnesses or associated symptoms through a MTDLs approach. Donepezil, whose interaction with s1 receptors in vivo has been ascertained by receptor occupancy studies in the human brain [94,158], is co-administered together with Memantine through prescription medicines (i.e., Namzaric). On this basis, the rational development of MTDLs with a s1 intentional targeting profile may lead to more important therapeutic actions. The amount of herein listed proteins, which are the object of the MTLDs development in association with the s1 receptor, is not intended to be exhaustive. Other proteins may be taken into consideration in the MTDLs development, considering the wide range of s1 receptor direct and indirect interactors. Cannabinoid type-2 (CB2) receptors are an example, with recent support from computational methods that point out a partial overlap of the s1 and CB2 receptors’ pharmacophores [159]. These data strongly suggest the adoption of a merging approach for the development of dual s1/CB2 receptors ligands for a synergistic exploitation of the pathways activated by the two targets in oncology and neurodegenerative diseases. A number of s ligands, besides interacting at the two subtypes (see Section 3.7), are able to modulate the efflux pump P-glycoprotein (P-gp) [150,160]. This double action is worthy of being more intentionally addressed, as it may serve as a strategy to face drug-resistant tumors: the compound overcomes P-gp, which is overexpressed in many resistant tumors and exerts its cytotoxic activity (as a s1 antagonist). Importantly, this same double action may also have a role in the treatment of CNS diseases through the bypass of the P-gp at the BBB. The waving interest in s receptors research increased during the COVD-19 pandemic, when the proteins were found as important key host dependency factors for coronavirus infections. However, while the exploitability of the s1 receptor as a druggable target against coronavirus still needs to be fully investigated and validated, it appears clear that this protein is involved in a plethora of pathways hampered in multifactorial CNS and cancer diseases, rendering the s1 receptor a full-fledged target for the development of multifunctional therapeutics.
https://www.mdpi.com/1422-0067/22/12/6359/htm
2. See also: Anavex Life Sciences Corp. Presents Data on Neuroprotective Evidence for ANAVEX 2-73, Lead Compound for Alzheimer's Disease
...ANAVEX 2-73 is not only active in and of itself, but is also a pro-drug. Its only metabolite, ANAVEX 19-144, is also active (in animal models)....
...ANAVEX 19-144, when administered prior to amyloid 25-35, protects against amyloid 25-35-induced amnesia in mice.
- ANAVEX 19-144 protects against amyloid 25-35-induced oxidative stress, measured by lipid peroxidation in hippocampal cells.
“It is hypothesized that cholinomimetic-only compounds would not have as much benefit as the mixed mechanism of the aminotetrahydrofurans, which may be potentiating. Interestingly, the pro drug and active drug effect of ANAVEX 2-73, which has ANAVEX 19-144 ‘embedded’ in it, may offer a longer duration of action,” said Dr. Tangui Maurice, PhD.....
https://www.biospace.com/article/releases/ana...se-405521/
3. Blarcamesine
It is a mixed ligand for sigma1/muscarinic receptors.
https://www.alzforum.org/therapeutics/blarcamesine
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