Why drug development is hard #34 — designer hallucinogens

NBOMe (2-(4-Bromo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl) methyl]ethanamine to you) is a potent hallucinogen, a member of the phenylethylamine series of hallucinogens.  Well that’s the same as saying the current Intel chips are a member of the Intel class of starting with the 8080. https://psychonautwiki.org/wiki/25B-NBOMe has the structure, but I count 2 methoxy groups and a bromine on the phenyl group and a methoxy benzyl group making the amine group a secondary amine.

How anyone came up with the structure will remain unknown to me as it was part of a PhD thesis written in 2003 — unfortunately in German —Ralf Heim (February 28, 2010). “Synthese und Pharmakologie potenter 5-HT2A-Rezeptoragonisten mit N-2-Methoxybenzyl-Partialstruktur. Entwicklung eines neuen Struktur-Wirkungskonzepts.” (in German). diss.fu-berlin.de. Retrieved 2013-05-10.

Like other hallucinogens (LSD, mescaline, psilocin) NBOMe binds to the 2A variety of serotonin receptor (aka 5HT2A — at least 16 serotonin receptors are known) and acts like LSD as an agonist.

Which brings me to Cell vol. 182 pp. 1574 – 1588 ’20 — https://www.cell.com/cell/fulltext/S0092-8674(20)31066-7, probably behind a paywall.  Which has beautiful cryoEM structures of 5HT2A bound to LSD, NBOMe and methiothepin, an inverse agonist.  To get pictures they had to stabilize the structure with a single chain variable fragment of an antibody (something that always makes me wonder how physiologic the structure obtained actually is).

Why use NBOMe as an example of how hard drug discovery is?  Well the binding site of LSD to 5HT2A is well known, and the paper has some beautiful pictures of LSD snuggled between the 7 transmembrane segments of 5HT2A.  What is remarkable about NBOMe is that it lies in the binding site in a completely different orientation.  Moreover NBOMe fits in a previously undescribed pocket between transmembrane segments #3 and #6 (TM3, TM6).  Actually I think NBOMe actually produces the pocket.

So even if you know the target of your drug (5HT2A) and how another drug hits the target you’re aiming for, this doesn’t help you in designing a newer and more potent drug.

Why drug discovery is so hard: Reason #22 — Drugs aren’t doing what we think they are

50 or so years ago, Cambridge apocrypha had it that Timothy Leary, put LSD into the punch at a party to observe its effects on social behavior (an early double blind experiment).  A student, having imbibed, decided he was God and could walk across Massachusetts avenue with impunity, losing his life in the process, his death being hushed up by Harvard.  It could have been an urban myth, but it was widely prevalent, showing that even the highly intelligent aren’t immune to this sort of thing.

So we all knew (and know) that LSD and other hallucinogens causes a degree of excitement.  We then assume that excitement is synonymous with increased brain activity, correct?  Wrong says [ Proc. Natl. Acad. Sci. vol. 109 pp. 1820 – 1821, 2138 – 2143 ’12 ] !

Hallucinogens like LSD and psilocybin bind to lots of neurotransmitter receptors (serotonin alone has at least 14, and this doesn’t count the splice variants).  Still, the best correlation of hallucinogenic activity is with agonist activity at one serotonin subtype, the serotonin 2A receptor (5HT2AR). In man, the psychedelic activity of psilocin is blocked by pretreatment with 5HT2AR antagonists.

There are now noninvasive methods to study brain activity in man.  The most prominent one is called BOLD, and is based on the fact that blood flow increases way past what is needed with increased brain activity.  This was actually noted by Wilder Penfield operating on the brain for epilepsy in the 30s.  When the patient had a seizure on the operating table (they could keep things under control by partially paralyzing the patient with curare) the veins in the area producing the seizure turned red.  Recall that oxygenated blood is red while the deoxygenated blood in veins is darker and somewhat blue.  This implied that more blood was getting to the convulsing area than it could use.

BOLD depends on slight differences in the way oxygenated hemoglobin and deoxygenated hemoglobin interact with the magnetic field used in magnetic resonance imaging (MRI).  The technique has had a rather checkered history, because very small differences must  be measured, and there is lots of manipulation of the raw data (never seen in papers) to be done.  10 years ago functional magnetic imaging (fMRI) was called pseudocolor phrenology.

Another newer technique called arterial spin labeling perfusion also measures blood flow.

Both techniques were used on 15 ‘experienced’ hallucinogen users, who received either placebo or psilocin (the active metabolite  of psyilocybin) IV.  The druggies also rated the intensity of their experiences.

The surprising finding is that decreases in blood flow (implying decreased neuronal activity) occured in areas of the brain ‘implicated’ (e.g. not proven) in psychedelic drug actions.  Even more interesting is that the intensity of the experience  correlated with decrements in blood flow.

This constitutes yet another example of why drug discovery is hard.  Even when we know the observable effects of a given drug, our theories of how the drug does what it does, can be widely off base — in this case bass ackwards.  So if you were screening for an antihallucinogen, the incorrect theory would lead you seriously astray.  This is why big pharma is dropping research on CNS drugs — they haven’t had much success, and the theories to guide them may be flat out wrong.