Neuroscience for Synthetic Chemists

Overview: Natural products, such as tetrodotoxin, kainic acid and morphine, have played a crucial role in the development of neuroscience. Using selected chemical syntheses as a framework, I will provide an introduction to neuroscience for chemists blended with an intense course in synthetic design ("Syntheseplanung"). The structure, function and synthesis of the following molecules will be analyzed: tetrodotoxin, saxitoxin, kainic acid, nicotine, epibatidine, coniine, tubocurarine, histrionicotoxin, ibotenic acid, strychnine, picrotine, chrysanthemic acid, ivermectin, muscarine, morphine, salvinorin A, THC, lysergic acid, forskolin, staurosporin, eglumegad, physostigmine, huperzin A, galanthamine, cocaine, reserpine, thapsigargin, ouabagenin, ryanodine, capsaicin, resiniferatoxin, retinal, carotene, menthol, santalol, camphor, and the prostaglandins. The structure and function of important ion channels, GPCRs, transporters and enzymes and their ligands will be discussed using PyMol files.

Goals: The goal of this course is to get as many synthetic chemists excited about neuroscience as possible (and a few neuroscientists stoked about synthesis). The importance of structural and pharmacological databases (PDB and IUPHAR, respectively) and the usefulness of the Reaxys database (and SciFinder) for synthetic planning will be demonstrated.

Requirements: A familiarity with synthetic organic chemistry and (named) chemical reactions, a mastery of the Nernst equation, and a willingness to learn more about one of the greatest, if not the greatest scientific challenges of our times: to figure out how the human brain works.

Problem Sets

The solution to the problem sets will be discussed every week on Tuesday at 18.00 in C4.005.

problem set 1
problem set 2
problem set 3
problem set 4
problem set 5
problem set 6
problem set 7 (please ignore the remark concerning the room)

Final exam

final exam results

questions catalogue concerning neurobiology

Handouts and Additional Files:

Introduction
Introduction
Further Reading:
A nice review on X-ray crystallography and its impact on modern biology: Shi
A nice review on cryo EM and its impact on modern biology: Leiro and Scheres
The Protein Data Base: http://pdb.org
The White database on transmembrane proteins with known structure: http://blanco.biomol.uci.edu/mpstruc/#Latest
The IUPHAR Pharmacology Data Base: http://www.guidetopharmacology.org

1. The Resting Potential, the Action Potential, and Voltage-Gated Ion Channels:
Notes:
Chapter 1
Structures:
KcsA, the archetypical potassium channel
KcsA blocked by a quaternary ammonium ion
Kv1.2, a voltage gated potassium channel
Kv1.2, two subunits
Agitoxin-2 from the Death Stalker Scorpion
NavAb, a bacterial sodium channel
Further Reading:
History of the action potential: Schwiening

2. Synaptic Transmission, Ligand-Gated Ion Channels, and Glutamate Receptors:
Notes:
Chapter 2
Structures:
GluA2 with a partial agonist
GluA2, two subunits
GluK2 LBD with kainic acid
NMDA receptor with glutamate and glycine

3. Pentameric Ligand-Gated Ion Channels:
Notes:
Chapter 3
Structures:
nAChR from an electric eel
nAChR model with nicotine
GABA-A receptor
GlyR model with strychnine
5-HT3, a serotonin receptor that is an ion channel
GluCl with ivermectin and picrotoxinin

4. Metabotropic Receptors and GPCRs:
Notes:
Chapter 4
Structures:
b2AR in complex with the heterotrimeric Gs and an agonist
M3 with the antagonist tiotropium
MOR with a covalently bound morphinan antagonist
D3 dopamine receptor with the antagonist eticlopride
5HT1b serotonin receptor with the agonist ergotamine
mGluR2 LBD dimer with eglumegad
GABA-B LBD dimer with GABA
Phorbol acetate bound to the C1 domain of PKC
Staurosporine bound to the catalytic domain of a PKC

5. Enzymes in Synaptic Transmission
Notes:
Chapter 5 updated January 21st
Structures:
AChE irreversibly inhibited by sarin
AChE inhibited by huperzine A
AChE inhibited by galanthamine

6. Transporters and Pumps
Notes:
Chapter 6
Structures:
Na/K-ATPase inhibited by ouabain
LeuT, a model of SERT, inhibited by sertraline
DAT inhibited by nortryptiline

7. Calcium in Neuroscience: Neurons and Muscles
Notes:
Chapter 7 updated February 2nd 2017
Structures:
SERCA inhibited by a thapsigargin derivative

8. Sensory Physiology
Notes:
Chapter 8
Structures:
TRPV1 with the capsaicin/vanilloid binding site indicated
Rhodopsin with 11-cis retinal covalently bound
Metarhodopsin II with all-trans retinal covalently bound
Opsin lacking retinal
Further Reading/Viewing:
A primer on vision: Vision