Indalpine

Key takeaways

Indalpine belongs to chemistry; place it in that map before memorising details.
Learn the definition first, then one example that makes the definition concrete.
Connect Indalpine to a quantity you can measure, compute or draw — that is where exam questions come from.
Reproduce the core statement of Indalpine from memory before moving on to harder problems.

Reference excerpt

Indalpine, sold under the brand name Upstène, is a selective serotonin reuptake inhibitor (SSRI) that was briefly marketed as an antidepressant for treatment of depression. It was marketed in France and a few other European countries. Indalpine is a selective serotonin reuptake inhibitor (SSRI) and antihistamine. Indalpine was invented by 1977 and was introduced for medical use in France in 1983. Two years later, in 1985, it was withdrawn from the market due to toxicity. Indalpine has sometimes been said to be the first SSRI. However, it was preceded by the SSRI zimelidine (Zelmid), which was invented in 1969 and was introduced to the market in 1981 (then similarly withdrawn due to toxicity in 1983).

Pharmacology

Pharmacodynamics Indalpine is a selective serotonin reuptake inhibitor (SSRI) and antihistamine.

Chemistry Indalpine is an indole and is structurally similar to tryptamines but is not a tryptamine itself.

Synthesis

Metalation of indole (1) using methyl magnesium iodide forms the organo-magnesium derivative (2) which reacts with 1-benzyloxycarbonyl-4-piperidyl-acetyl chloride (3) to give (4). Acid-catalyzed removal of the benzyloxycarbonyl (Cbz) protecting group gives the ketone (5). Reduction with lithium aluminium hydride yields indalpine.

History A patent for indalpine was filed in 1976 and granted in 1977. It was marketed by Fournier Frères-Pharmuka in France in 1983. The drug was withdrawn from the market due to toxicity, including neutropenia or agranulocytosis and hepatic carcinogenicity, 2 years later in 1985. The drug was never introduced in the United States. Indalpine was derived from structural modification of antihistamines. It was invented in 1977 by the pharmacologists Le Fur and Uzan at Pharmuka, a small French pharmaceutical firm, who credit Baron Shopsin and his colleagues at NYU-Bellevue or NYU School of Medicine in New York with providing the basis for their work. They were particularly influenced by the series of "synthesis inhibitor studies" carried out by Shopsin's team during the early to mid 1970s, and in particular, the clinical report by Shopsin et al. (1976) relating to PCPA's rapid reversal of antidepressant response to tranylcypromine in depressed patients. This led to an understanding of the role of the monoamine neurotransmitter serotonin (5-hydroxytryptamine, or 5HT) in the therapeutic effects of the available tricyclic and MAOI class antidepressants. The studies led to widespread recognition of a serotonin hypothesis of depression, contradicting theories that promoted the role of norepinephrine. While citalopram and zimelidine were developed in the early 1970s, it was Pharmuka's indalpine that was first to reach the market. Baron Shopsin was recruited as consultant to Pharmuka throughout a research and development process that resulted in the marketing of indalpine in France and then worldwide, in 1982. With FDA approval of Pharmuka's Investigational New Drug (IND) submission to conduct clinical studies with indalpine and viqualine, Shopsin carried out and published the first clinical trials with these drugs in depressed outpatients in the United States. Astra's SSRI zimelidine was marketed within a year (1983), but the next crop of SSRIs did not become commercially available until the 1986 marketing of fluvoxamine in Belgium by Duphar, followed by approval in the United States later that year. Lilly's fluoxetine (Prozac) was approved in the United States in 1987. Meanwhile, zimelidine had been withdrawn soon after its marketing in 1983 due to the emergence of Guillain–Barré syndrome, a serious neurological disease. With lingering concerns among some Common Market countries and activist groups about the potential of SSRIs to induce adverse effects, and the reported association between indalpine and hematological effects, which emerged in the aftermath of Pharmuka's take over by Rhône Poulenc, indalpine was abruptly taken off the market by Rhône Poulenc. Irish psychiatrist David Healy characterized indalpine as being "born at the wrong time" during a period when "indalpine and psychiatry was under siege" by different interest groups in some of the Common Market countries. In line with indalpine's fate, research and development was halted relating to the two other 4-alkylpiperidine derivatives developed by Pharmuka, viqualine (a serotonin releasing agent) and pipequaline (a GABAA receptor positive allosteric modulator), both in different stages of development at the time. In 2010, revision of this molecular motif yielded SERT inhibitors with nanomolar and subnanomolar IC50 values.

Society and culture

Names Indalpine is the generic name of the drug and its INNTooltip International Nonproprietary Name and BANTooltip British Approved Name. It was also known by its developmental code name LM-5008. The drug was sold under the brand name Upstène.

Illustrations

Worked examples

Example 1 — a first encounter with Indalpine

Start with the simplest possible case. Write down what Indalpine claims or describes in one sentence, then invent the smallest concrete situation in which that sentence is true. In chemistry, the smallest case is usually a single object, a single equation or a single measurement. Check that every symbol or term in your sentence has a meaning in that case.

Example 2 — changing one variable

Take the situation from Example 1 and change exactly one quantity: double it, halve it, or set it to zero. Predict what should happen to Indalpine before you calculate. Comparing your prediction with the result is the fastest way to find out whether you understand the idea or only the words.

Example 3 — an exam-style question

Typical questions about Indalpine ask you to (a) state it precisely, (b) apply it to given data, and (c) explain a limitation. Practise writing all three answers in under five minutes; the third part is what separates a full-mark answer from an average one.

Applications of Indalpine

In research: Indalpine appears in chemistry research whenever the underlying quantities have to be modelled precisely. Papers usually cite it as a starting assumption and then explore where it breaks down.
In technology and industry: Engineering practice reuses Indalpine in design rules, simulations and safety margins. Knowing the idea lets you read a specification sheet and understand why the numbers look the way they do.
In the classroom: Indalpine is common in secondary-school and first-year university syllabi. It links to neighbouring topics 4-Piperidinyl compounds, Antidepressants, Antihistamines, so understanding it makes those chapters shorter.
In everyday life: Look for Indalpine outside the textbook — in sport, cooking, traffic, electronics or the sky above you. An example you found yourself is remembered far longer than one you were given.

How to study Indalpine in 20 minutes

Read the reference excerpt below once, without taking notes.
Close the page and write down what Indalpine means in your own words.
Compare your version with the excerpt and mark what you missed.
Work through the three examples above with pen and paper.
Explain Indalpine out loud to somebody else — or to Teacher Smith in the lgStudy chat.

Frequently asked questions

What is Indalpine in simple terms?

Indalpine, sold under the brand name Upstène, is a selective serotonin reuptake inhibitor (SSRI) that was briefly marketed as an antidepressant for treatment of depression. It was marketed in France and a few other European countries.

Why does Indalpine matter?

Because it connects several chemistry ideas at once: it gives you a definition you can apply, a quantity you can calculate, and a way to check whether a result is plausible.

How should I study Indalpine?

Read the excerpt, restate it from memory, then work through the examples and applications listed on this page. The five-step study plan above takes about twenty minutes.

What does this page cover?

It gives you a compact reference excerpt plus original lgStudy explanations, examples, applications and study material on Indalpine.