The spinal reflex depressant mechanism of tolperisone and some of its structural analogs with central muscle relaxant action was investigated. Tolperisone (50 -400 M), eperisone, lanperisone, inaperisone, and silperisone (25-200 M) dose dependently depressed the ventral root potential of isolated hemisected spinal cord of 6-day-old rats. The local anesthetic lidocaine (100 -800 M) produced qualitatively similar depression of spinal functions in the hemicord preparation, whereas its blocking effect on afferent nerve conduction was clearly stronger. In vivo, tolperisone and silperisone as well as lidocaine (10 mg/kg intravenously) depressed ventral root reflexes and excitability of motoneurons. However, in contrast with lidocaine, the muscle relaxant drugs seemed to have a more pronounced action on the synaptic responses than on the excitability of motoneurons. Whole-cell measurements in dorsal root ganglion cells revealed that tolperisone and silperisone depressed voltage-gated sodium channel conductance at concentrations that inhibited spinal reflexes. Results obtained with tolperisone and its analogs in the [3 H]batrachotoxinin A 20-␣-benzoate binding in cortical neurons and in a fluorimetric membrane potential assay in cerebellar neurons further supported the view that blockade of sodium channels may be a major component of the action of tolperisone-type centrally acting muscle relaxant drugs. Furthermore, tolperisone, eperisone, and especially silperisone had a marked effect on voltagegated calcium channels, whereas calcium currents were hardly influenced by lidocaine. These data suggest that tolperisonetype muscle relaxants exert their spinal reflex inhibitory action predominantly via a presynaptic inhibition of the transmitter release from the primary afferent endings via a combined action on voltage-gated sodium and calcium channels.2-Methyl-1-(4-methylphenyl)-3-(1-piperidinyl)-1-propanone hydrochloride (tolperisone) is an old, centrally acting muscle relaxant drug that is mainly used for treating muscle spasticities of neurological origin and painful muscle spasms due to rheumatologic conditions. Besides being an effective antispastic agent (Pratzel et al., 1996;Dulin et al., 1998), tolperisone also has analgesic activity in rodents (Sakaue et al., 2004) and in humans (Svensson et al., 2003). It possesses relatively few side effects in humans (Dulin et al., 1998). Other propiophenone muscle relaxants include 1-(4-ethylphenyl)-2-methyl-3-(1-piperidinyl)-1-propanone hydrochloride (eperisone), which is also a registered drug (Bose, 1999), and (Ϫ)-2-(R)-methyl-3-(1-pyrrolidinyl)-1-[4-(trifluoromethyl)phenyl]-propanone hydrochloride (lanperisone; Sakitama et al., 1997) and 1-(4-ethylphenyl)-2-methyl-3-(1-pyrrolidinyl)-1-propanone hydrochloride (inaperisone; Morikawa et al., 1992), two agents that had been tested in human phase III studies but not introduced into the clinical practice. 1-[(4-Fluorobenzyl)dimethylsilylmethyl]piperidine hydrochloride (silperisone), a sila analog of tolperisone (Farkas et ...

No abstract

No abstract

(4-Benzylpiperidine-1-yl)-(6-hydroxy-1H-indole-2-yl)-methanone (6a) derived from (E)-1-(4-benzylpiperidin-1-yl)-3-(4-hydroxy-phenyl)-propenone (5) was identified as a potent NR2B subunit-selective antagonist of the NMDA receptor. To establish the structure-activity relationship (SAR) and to attempt the improvement of the ADME properties of the lead, a series of compounds were prepared and tested. Several derivatives showed low nanomolar activity both in the binding and in the functional assay. In a formalin-induced hyperalgesia model in mice, 6a and (4-benzylpiperidine-1-yl)-[5(6)-hydroxy-1H-benzimidazol-2-yl]-methanone (60a) were as active as besonprodil (2) after oral administration. A CoMSIA model was developed based on binding data of a series of indole- and benzimidazole-2-carboxamides.

No abstract

No abstract

Negative allosteric modulators (NAM) of metabotropic glutamate receptor 5 (mGluR5) have been implicated as a potential pharmacotherapy for a number of psychiatric diseases, including anxiety and depression. Most of the mGluR5 NAM clinical candidates can be characterized by the central acetylenic moiety that connects the terminal pharmacophores. Identification of a sulfoquinoline hit via high throughput screening (HTS) followed by optimization provided a 4-phenyl-3-aryl-sulfoquinoline lead compound with the minimal pharmacophore. Optimization of the core and aryl appendages was performed by scanning and matrix libraries synthesized by the multiple parallel synthesis approach. Biological evaluation of matrix libraries provided a number of potent, metabolically stable, and in vivo active compounds. One of these compounds, 25 showed high efficacy and safety in preclinical in vivo models; this allowed its nomination as a novel, nonacetylenic mGluR5 NAM clinical candidate. Compound 25 was advanced to first-in-man trials for the treatment of psychiatric conditions.

No abstract