listener serotonin receptors ambrose

Serotonin Receptor Ligands

Introduction

  • Instructor: Elizabeth A. Ambrose

  • Course: Phar 6542

  • Institution: College of Pharmacy, University of Minnesota

  • Theme: Driven to Discover™

Learning Objectives for This Session

  • Understanding the Major Serotonin Receptor Subtypes

  • Analyzing the Structure and Mechanisms of LSD (Lysergic Acid Diethylamide)

  • Discussing Therapeutic Analogs of LSD

  • Exploring 5-HT1A Partial Agonists

  • Investigating 5-HT2C Agonists & Antagonists

  • Examining 5-HT3 Antagonists

  • Identifying 5-HT4 Agonists

  • Summary of key concepts

What is Serotonin and How is it Made?

  • Serotonin (5-HT, 5-hydroxytryptamine): Neurotransmitter derived from the amino acid tryptophan.

  • Synthesis pathway:
      1. L-Tryptophan is ohydroxylated by tryptophan hydroxylase to form 5-hydroxytryptophan (5-HTP).
      2. 5-HTP is decarboxylated by aromatic amino acid decarboxylase to yield serotonin.
      3. Serotonin can be further metabolized to 5-hydroxyindole-acetic acid (5-HIAA) by monoamine oxidase (MAO).
      4. Melatonin is formed from serotonin through the action of the enzyme N-acetyltransferase and O-methyltransferase.

Serotonin Receptors

Overview of Serotonin (5-HT) Receptors

  • **Key Receptor Subtypes: **
      - 5-HT1A:
        - Physiological Response: Increased K+ conductance, hyperpolarization.
        - Associated Disorders: Anxiety, depression.
      - 5-HT1B:
        - Physiological Response: Increased K+ conductance, hyperpolarization.
        - Associated Disorders: Migraine.
      - 5-HT1D:
        - Physiological Response: Increased K+ conductance, hyperpolarization.
        - Associated Disorders: Migraine.
      - 5-HT2C:
        - Physiological Response: Increased intracellular Ca2+.
        - Associated Disorders: Obesity.
      - 5-HT3:
        - Physiological Response: Fast depolarization.
        - Associated Disorders: Emesis.
      - 5-HT4:
        - Physiological Response: Increased K+ conductance, hyperpolarization.
        - Associated Disorders: Gastrointestinal (GI) disorders.

Serotonin Receptor Subtypes: Agonists and Antagonists

Serotonin Receptor 5-HT1A

  • Agonists (full or partial):
      - Buspirone, ergot alkaloids, gepirone, methysergide, quetiapine, ziprasidone, SPARIs

  • Antagonists:
      - Alprenolol, asenapine, propranolol.

Serotonin Receptor 5-HT1B

  • Agonists:
      - Ergot alkaloids, triptans.

  • Antagonists:
      - Alprenolol, asenapine, propranolol.

Serotonin Receptor 5-HT1D

  • Agonists:
      - Ergot alkaloids, triptans.

  • Antagonists:
      - Ketanserin, ritanserin.

Serotonin Receptor 5-HT2A

  • Agonists:
      - Hallucinogens such as LSD, mescaline, psilocin, psilocybin.

  • Antagonists:
      - Antipsychotic and anxiolytic medications: Aripiprazole, clozapine, iloperidone, mirtazapine, nefazodone, olanzapine, quetiapine, risperidone, trazodone, ziprasidone.

Serotonin Receptor 5-HT2B

  • Agonists:
      - Agomelatine, asenapine, LSD (PNS), ritanserin, tegaserod.

  • Antagonists:
      - Toxicity observed with fenfluramine and norfenfluramine.

Serotonin Receptor 5-HT2C

  • Agonists:
      - Lorcaserin, fenfluramine, norfenfluramine.

  • Antagonists:
      - Clozapine, mianserin, cyproheptadine, fluoxetine, mirtazapine, trazodone, olanzapine, risperidone, tramadol.

Serotonin Receptor 5-HT3

  • Antagonists:
      - Ondansetron, tropisetron, granisetron, with various antidepressant effects noted in drugs like bupropion, mirtazapine, vortioxetine; antipsychotics such as clozapine, olanzapine, and quetiapine.

Serotonin Receptor 5-HT4

  • Agonists:
      - Metoclopramide, tegaserod, cisapride.

  • Antagonists:
      - No current clinical use in the market.

LSD (Lysergic Acid Diethylamide)

Mechanism of Action and Pharmacological Properties

  • Agonism of 5-HT2A: Psychedelic effects attributed to this receptor's activation.

  • Ergoline Core Structure: Responsible for various pharmacological effects.

  • Nonselective: Hits multiple 5-HT receptors and agonizes dopamine receptors.

  • Adverse Effects: Nausea, drowsiness, ischemia, rebound headaches.

Derivatives of LSD

  • Ergonovine: A natural product derived from ergot; causes uterine contractions to counteract postpartum bleeding.

  • Methylergonovine: Synthetic; used to control bleeding and treat migraines.

  • Methysergide: Prodrug of methylergonovine; withdrawn from the U.S. market for safety reasons.

Synthesis and Production of LSD

  • Synthesis: Primarily occurs in clandestine labs with effective yield from ergotamine tartrate; 1 kg of pure LSD can be synthesized from 5 kg of ergotamine.

  • Usage: >99% of LSD doses are orally ingested, such as in various forms: blotter paper, gummies, tablets.

Effects of LSD

  • Physical Effects: Blurred vision, diaphoresis, heart palpitations.

  • Psychological Effects: Euphoria, altered perceptions, hallucinations.

  • Onset: Approximately 30-60 minutes with peak effects at 1-6 hours and usually dissipating by 8-12 hours.

  • Flashbacks: Possible at higher doses, particularly in patients with preexisting conditions like schizophrenia.

Key Points on Serotonin Receptor Ligands

  • Ergot Alkaloids: Serve as a crucial foundation in exploring serotonin interactions leading to compounds such as LSD.

  • 5-HT1A Partial Agonists: Primarily target anxiety, not suitable for acute anxiety episodes.

  • 5-HT2A Agonists and Antagonists: Exhibit a wide range of actions, with psychedelics activating and neuroleptics providing therapeutic effects.

  • 5-HT2C Agonists: Contribute to obesity treatment but come with safety concerns regarding cardiac health.

  • 5-HT3 Antagonists: Play a valuable role in the management of nausea and emesis, particularly in oncology.

  • 5-HT4 Agonists: Affect gastrointestinal motility and promote anti-nausea effects while often exhibiting high placebo response rates and various side effects.