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Conformationally Restricted σ1 Receptor Antagonists from (-)-Isopulegol. 2023

Luca Blicker, and Rafael González-Cano, and Erik Laurini, and Francisco R Nieto, and Judith Schmidt, and Dirk Schepmann, and Sabrina Pricl, and Bernhard Wünsch
Institut für Pharmazeutische und Medizinische Chemie, Westfälische Wilhelms-Universität Münster, Corrensstraße 48, D-48149 Münster, Germany.

Antagonists at σ1 receptors have great potential for the treatment of neuropathic pain. Starting from monoterpene (-)-isopulegol (1), aminodiols 8-11 were obtained and transformed into bicyclic 13-16 and tricyclic ligands 19-22. Aminodiols 8-11 showed higher σ1 affinity than the corresponding bicyclic 13-16 and tricyclic derivatives 19-22. (R)-configuration in the side chain of aminodiols (8 and 10) led to higher σ1 affinity than (S)-configuration (9 and 11). 4-Benzylpiperidines (b-series) revealed higher σ1 affinity than 4-phenylbutylamines (a-series). Aminodiol 8b showed very high σ1 affinity (Ki = 1.2 nM), excellent selectivity over σ2 receptors, and promising logD7.4 (3.05) and lipophilic ligand efficiency (5.87) values. Molecular dynamics simulations were conducted to analyze the σ1 affinity and selectivity on an atomistic level. In the capsaicin assay, 8b exhibited similar antiallodynic activity to the prototypical σ1 antagonist S1RA. The antiallodynic activity of 8b was removed by co-application of the σ1 agonist PRE-084, proving σ1 antagonism being involved in the antiallodynic effect.

UI MeSH Term Description Entries
D008024 Ligands A molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule, e.g., an antigen binding to an antibody, a hormone or neurotransmitter binding to a receptor, or a substrate or allosteric effector binding to an enzyme. Ligands are also molecules that donate or accept a pair of electrons to form a coordinate covalent bond with the central metal atom of a coordination complex. (From Dorland, 27th ed) Ligand
D000081005 Cyclohexane Monoterpenes Monoterpenes that include a cyclohexane ring in their structure. Monoterpenes, Cyclohexane
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D017480 Receptors, sigma A class of cell surface receptors recognized by its pharmacological profile. Sigma receptors were originally considered to be opioid receptors because they bind certain synthetic opioids. However they also interact with a variety of other psychoactive drugs, and their endogenous ligand is not known (although they can react to certain endogenous steroids). Sigma receptors are found in the immune, endocrine, and nervous systems, and in some peripheral tissues. Opioid Receptors, sigma,Receptors, Opioid, sigma,Receptors, sigma Opioid,sigma Receptors,sigma Receptor,Receptor, sigma,sigma Opioid Receptors
D056004 Molecular Dynamics Simulation A computer simulation developed to study the motion of molecules over a period of time. Molecular Dynamics Simulations,Molecular Dynamics,Dynamic, Molecular,Dynamics Simulation, Molecular,Dynamics Simulations, Molecular,Dynamics, Molecular,Molecular Dynamic,Simulation, Molecular Dynamics,Simulations, Molecular Dynamics

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