Synthesis of tropane-based σ receptor antagonists with antiallodynic activity.

Following the concept of conformational restriction to obtain high affinity σ ligands, the piperidine ring of eliprodil was replaced by the bicyclic tropane system and an exocyclic double bond was introduced. The envisaged benzylidenetropanes 9 were prepared by conversion of tropanone 10 into the racemic mixture of (Z)-14 and (E)-14. Reaction of racemate (Z)-14/(E)-14 with enantiomerically pure (R)- or (S)-configured 2-phenyloxirane provided mixtures of diastereomeric β-aminoalcohols (R,Z)-9 and (R,E)-9 as well as (S,Z)-9 and (S,E)-9, which were separated by chiral HPLC, respectively.

Chemoenzymatic synthesis of 2,6-disubstituted tetrahydropyrans with high σ receptor affinity, antitumor and analgesic activity.

1,3-Dioxanes 1 and cyclohexanes 2 bearing a phenyl ring and an aminoethyl moiety in 1,3-relationship to each other represent highly potent σ receptor antagonists. In order to increase the chemical stability of the acetalic 1,3-dioxanes 1 and the polarity of the cyclohexanes 2, tetrahydropyran derivatives 3 equipped with the same substituents were designed, synthesized and pharmacologically evaluated. The key step of the synthesis was a lipase-catalyzed enantioselective acetylation of the alcohol (R)-5 leading finally to enantiomerically pure test compounds 3a-g.

Sigma-1 Receptor Inhibition Reduces Neuropathic Pain Induced by Partial Sciatic Nerve Transection in Mice by Opioid-Dependent and -Independent Mechanisms.

Sigma-1 (σ) receptor antagonists are promising tools for neuropathic pain treatment, but it is unknown whether σ receptor inhibition ameliorates the neuropathic signs induced by nerve transection, in which the pathophysiological mechanisms and response to drug treatment differ from other neuropathic pain models. In addition, σ antagonism ameliorates inflammatory pain through modulation of the endogenous opioid system, but it is unknown whether this occurs during neuropathic pain. We investigated the effect of σ inhibition on the painful hypersensitivity associated with the spared nerve injury (SNI) model in mice.

Synthesis, Receptor Affinity, and Antiallodynic Activity of Spirocyclic σ Receptor Ligands with Exocyclic Amino Moiety.

In order to detect novel σ receptor ligands, the rigid spiro[[2]benzopyran-1,1'-cyclohexan]-4'-one was connected with amino moieties derived from σ receptor preferring lead compounds resulting in mixtures of trans- and cis-configured amines 6, 18, and 27. In a four step synthesis the methyl acetals 6 were converted into fluoroethyl derivatives 13 and 30. The most promising σ receptor ligand is the methyl acetal 6a bearing a 2,4-dimethylbenzylamino moiety.

Effects of Tetrodotoxin in Mouse Models of Visceral Pain.

Visceral pain is very common and represents a major unmet clinical need for which current pharmacological treatments are often insufficient. Tetrodotoxin (TTX) is a potent neurotoxin that exerts analgesic actions in both humans and rodents under different somatic pain conditions, but its effect has been unexplored in visceral pain. Therefore, we tested the effects of systemic TTX in viscero-specific mouse models of chemical stimulation of the colon (intracolonic instillation of capsaicin and mustard oil) and intraperitoneal cyclophosphamide-induced cystitis.

Modulation of peripheral μ-opioid analgesia by σ1 receptors.

We evaluated the effects of σ1-receptor inhibition on μ-opioid-induced mechanical antinociception and constipation. σ1-Knockout mice exhibited marked mechanical antinociception in response to several μ-opioid analgesics (fentanyl, oxycodone, morphine, buprenorphine, and tramadol) at systemic (subcutaneous) doses that were inactive in wild-type mice and even unmasked the antinociceptive effects of the peripheral μ-opioid agonist loperamide. Likewise, systemic (subcutaneous) or local (intraplantar) treatment of wild-type mice with the selective σ1 antagonists BD-1063 [1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine dihydrochloride] or S1RA [4-[2-[[5-methyl-1-(2-naphthalenyl)1H-pyrazol-3-yl]oxy]ethyl] morpholine hydrochloride] potentiated μ-opioid antinociception; these effects were fully reversed by the σ1 agonist PRE-084 [2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate) hydrochloride], showing the selectivity of the pharmacological approach.

Potentiation of morphine-induced mechanical antinociception by σ₁ receptor inhibition: role of peripheral σ₁ receptors.

We studied the modulation of morphine-induced mechanical antinociception and side effects by σ₁ receptor inhibition. Both wild-type (WT) and σ₁ receptor knockout (σ₁-KO) mice showed similar responses to paw pressure (100-600 g). The systemic (subcutaneous) or local (intraplantar) administration of σ₁ antagonists (BD-1063, BD-1047, NE-100 and S1RA) was devoid of antinociceptive effects in WT mice.

Role of sigma-1 receptors in paclitaxel-induced neuropathic pain in mice.

Unlabelled: Sigma-1 (σ(1)) receptors play a role in different types of pain and in central sensitization mechanisms; however, it is unknown whether they are involved in chemotherapy-induced neuropathic pain. We compared the ability of paclitaxel to induce cold (acetone test) and mechanical (electronic Von Frey test) allodynia in wild-type (WT) and σ(1) receptor knockout (σ(1)-KO) mice. We also tested the effect on paclitaxel-induced painful neuropathy of BD-1063 (16-64 mg/kg, subcutaneously) and S1RA (32-128 mg/kg, subcutaneously), 2 selective σ(1) receptor antagonists that bind to the σ(1) receptor with high affinity and competitively.

Tetrodotoxin (TTX) as a therapeutic agent for pain.

Tetrodotoxin (TTX) is a potent neurotoxin that blocks voltage-gated sodium channels (VGSCs). VGSCs play a critical role in neuronal function under both physiological and pathological conditions. TTX has been extensively used to functionally characterize VGSCs, which can be classified as TTX-sensitive or TTX-resistant channels according to their sensitivity to this toxin.

Sigma-1 receptors are essential for capsaicin-induced mechanical hypersensitivity: studies with selective sigma-1 ligands and sigma-1 knockout mice.

We evaluated the role of sigma(1) receptors on capsaicin-induced mechanical hypersensitivity and on nociceptive pain induced by punctate mechanical stimuli, using wild-type and sigma(1) receptor knockout (sigma(1)-KO) mice and selective sigma(1) receptor-acting drugs. Mutation in sigma(1)-KO mice was confirmed by PCR analysis of genomic DNA and, at the protein level, by [(3)H](+)-pentazocine binding assays. Both wild-type and sigma(1)-KO mice not treated with capsaicin showed similar responses to different intensities of mechanical stimuli (0.

Tetrodotoxin inhibits the development and expression of neuropathic pain induced by paclitaxel in mice.

We evaluated the effect of low doses of systemically administered tetrodotoxin (TTX) on the development and expression of neuropathic pain induced by paclitaxel in mice. Treatment with paclitaxel (2mg/kg, i.p.