7.4.4.1 The Clinical–Molecular Interface: Epilepsy and
Voltage-Gated Na+Channels
Case History. “My seizures start without any warning. All of a sudden, I hear
Barney Rubble talking to Fred Flintstone. The Flintstones was my favourite television
cartoon when I was a child, and I really loved Barney Rubble. I can hear them talking.
Barney always says ‘Hello neighbour ... What are you up to today, Fred?’ Fred replies
‘Hiya Barney, ol’ Pal ...’ As soon as I hear Barney Rubble, I know that I am going to
have a seizure. My co-workers say that I stand motionless. I stare straight ahead, some-
times making smacking sounds with my lips. It lasts about one minute. Afterwards,
I blink my eyes a few times and shake my head. About 20 minutes later I am back to
normal.”
Initially, this individual had been given phenobarbital, the GABAergic drug; it had
done nothing for his seizures. However, when he received carbamazepine, the Na+chan-
nel antagonist, his seizures stopped immediately. As long as he was on this medication
he had no seizures.
7.4.5 Targeting the Potassium Channel Protein: AgonistsAlthough K+channels share significant structural similarities with voltage-gated Na+
and Ca^2 +channels, the latter have received greater attention than the K+channel in drug
design. This probably arises from the fact that K+channel agents are designed as ago-
nists (or openers), whereas the Na+and Ca^2 +channel agents are designed as antagonists
(or blockers). (The Na+ and Ca^2 + ion channels transport cations into electrically
excitable cells; the K+channel transports cations out of electrically excitable cells.)
Conceptually, it is easier to design antagonists than agonists, since it is simpler to
“break machines rather than make them work better.”
Despite these challenges, the area of K+channel openers (PCOs) is emerging as an
active area of drug design. Over the past 5–10 years, eight novel structural classes of
PCOs have received systematic development: benzopyrans (e.g., cromakalim,7.27),
cyanoguanidines (e.g., pinacidil,7.28), thioformamides (e.g., aprikalim,7.29), pyridyl
nitrates (e.g., nicorandil,7.30), benzothiadiazines (e.g., diazoxide,7.31), pyrimidine
sulphates (e.g., minoxidil sulphate,7.32), tertiary carbinols, and dihydropyridines.
These various classes have been subjected to analog preparation with compound
optimization via structure–activity studies.
ENDOGENOUS CELLULAR STRUCTURES 423