Igmesine (JO-1,784) is a

sigma receptor Sigma receptors (σ-receptors) are protein cell surface receptors that bind ligands such as 4-PPBP (4-phenyl-1-(4-phenylbutyl) piperidine), SA 4503 (cutamesine), ditolylguanidine, dimethyltryptamine, and siramesine. There are two subtypes, ...

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ag ...

( IC₅₀ = 39 nM (rat brain)). It has

neuroprotective Neuroprotection refers to the relative preservation of neuronal structure and/or function. In the case of an ongoing insult (a neurodegenerative insult) the relative preservation of neuronal integrity implies a reduction in the rate of neuronal los ...

and

antidepressant Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common Side effect, side-effects of antidepressants include Xerostomia, dry mouth, weig ...

-like effects in animal studies, as well as

nootropic Nootropics ( , or ) (colloquial: smart drugs and cognitive enhancers, similar to adaptogens) are a wide range of natural or synthetic dietary supplement, supplements or drugs and other substances that are claimed to improve cognitive function ...

effects in models of age-related cognitive decline. In two phase II

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, diet ...

s, igmesine was found to be effective in the treatment of depression and was as active as the comparator

fluoxetine Fluoxetine, sold under the brand names Prozac and Sarafem, among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used for the treatment of major depressive disorder, obsessive–compulsive diso ...

. However, in a large phase III clinical trial, igmesine failed to show significant effectiveness for depression. The drug has not been developed further.

Synthesis

Use patent designated in conjunction with SSRI:Thomas Gary Heffner, et al. (Eli Lilly and Co, Warner Lambert Co LLC). Igmesine synthesis

The first step involves a base catalysed alkylation between 2-phenylbutyric acid 0-27-7(1) and cinnamyl bromide 392-24-9(2) giving 2-ethyl-2,5-diphenylpent-4-enoic acid
CID:53783865
(3). Stepwise treatment of the carboxylic acid with

thionyl chloride Thionyl chloride is an inorganic compound with the chemical formula . It is a moderately volatile, colourless liquid with an unpleasant acrid odour. Thionyl chloride is primarily used as a chlorinating reagent, with approximately per year bein ...

and sodium azide followed by heating of this compound in an aprotic solvent causes the

Curtius rearrangement The Curtius rearrangement (or Curtius reaction or Curtius degradation), first defined by Theodor Curtius in 1885, is the thermal decomposition of an acyl azide to an isocyanate with loss of nitrogen gas. The isocyanate then undergoes attack by a v ...

of the acyl azide (4) to the

isocyanate In organic chemistry, isocyanate is the functional group with the formula . Organic compounds that contain an isocyanate group are referred to as isocyanates. An organic compound with two isocyanate groups is known as a diisocyanate. Diisocyan ...

intermediate (5). The reduction of the isocyanate was carried out with

lithium aluminium hydride Lithium aluminium hydride, commonly abbreviated to LAH, is an inorganic compound with the chemical formula Li Al H4. It is a white solid, discovered by Finholt, Bond and Schlesinger in 1947. This compound is used as a reducing agent in organic ...

affording the corresponding N-methylamine, i.e. N-Methyl-3,6-diphenylhex-5-en-3-amine
CID:53758312
(6). Schotten-Baumann reaction with cyclopropanoyl chloride 023-34-1gives the corresponding amide (7). A second step with

reduces the amide carbonyl completing the synthesis of igmesine (8).

References

{{Sigma receptor modulators Amines Alkene derivatives Cyclopropanes Sigma agonists