I've a question that's been puzzling me for at least a few months. I hope it's pertinent enough to fit in this thread, but the question is thus:
Considering the incogitable immensity of chemical space and the imponderable number of theoretically conceivable molecules or compounds one may synthesise, why is there such a dearth of lysergamides in existence or at least known to science?
I'm not a chemist, but a mere dilettante or hobbyist, who is baffled and lost at anything more exacting and arduous than, say, mescaline's total synthesis, so am far from capable of a convoluted synthesis of any of these complex molecules, like LSD-25 or ALD-52.
But why haven't the Shulgins or Nichols of the world—obviously capable of devising or synthesizing any compound they focus their profound intelligence and attention toward—not added anything substantive to the bizarrely paltry and nearly barren list of psychedelic lysergamides?
David Nichols, for example, has discovered an impressive array of serotonergic psychedelics that behave pharmacologically similar to LSD and its cognates. Yet, such an enviable chemistry wunderkind like himself has not been able to add much, if anything, noteworthy to the set of LSD's consanguineous compounds, but only develop pharmacological imitations without structural propinquity or molecular affinity or significant chemical consonance.
What's precluding a sufficiently erudite and gifted organic or medicinal chemist from churning out new bioactive psychedelic lysergamides or simply doing some permutation to the molecular structure of an extant compound to yield a novel derivative?
May the issue reside in the "base structure" (pardon me if the terminology isn't scientifically accurate or de rigueur) of these LSD-like compounds simply not being conducive or amenable to many theoretic alterations, modifications, etc., (like amphetamines, phenyltropanes, arylcyclohexylamines, opioids, etc) from which one may derive new drugs?
Or is the obstacle chemists face more to do with a difficulty with toying with unique configurations of these compounds, by dint of their sheer difficulty to synth or play around with molecularly?
It seems curious, because there is a seemly inexhaustible family of benzodiazepines, barbiturates, substituted amphetamines, etc. The paucity of never-before-encountered lysergamides seems so diminutive in comparison that a layman—like moi—couldn't possibly not be astonished at this unusual observation. It's outré.
To reiterate, is the limited quantity of lysergamides compared to, say, the abundance of barbiturates a result of the latter having a molecular base or backbone, so to say, that permits more alterations and derivatives than that of the former? Or is the relative non-complexity of the latter the reason its agnates greatly outnumber the former's? Is the answer some degree of both? Or is there some chemical explanation which I have overlooked or failed to mention that is at play here in this relative deficiency of lysergamides?
(I suppose my questions can be appropriately extended to other small families of compounds, like quinazolinones, salvinorin analogues, etc. But, for the sake of not diverging far from the topic of discussion, I shan't comment on these other, similarly austere chemical families.)
I'd appreciate any scientific justification that may exist for this impressive disparity between chemical families' populations. I haven't the chemical erudition to research this intriguing topic alone. My father, I'll say, is a brilliant biochemist with a doctorate from Durham, but he's thousands of miles away in Dhaka and is so absorbed in work he probably could not expend the time necessary to edify me.
Anyway, thanks to whomever reads my admittedly circumlocutory and prolix comment. It was hurriedly and extemporaneously composed, if you'll excuse me.
Tout À Vous,
Dnyanesh (NdP)
