From: sknight@tartarus.uwa.edu.au (Sam Knight) Newsgroups: alt.psychoactives Subject: Re: LSD analogues (was re: ALD-52) Date: 3 Oct 1994 12:33:28 GMT Message-ID: <36otmo$jfn@styx.uwa.edu.au> Christopher Hemming (CJHEMMIN@SCIENCE.watstar.uwaterloo.ca) wrote: : While we're on the subject of LSD analogues, I understand that replacing : the methyl group on nitrogen 6 with ethyl, allyl or propyl results in : compounds of similar, or even higher (by a factor of 2-3) potency. Is : this right? I'm pretty sure I've actually looked up the paper, but of : course it was just a glance at it. So, is that right? I have seen that too. The reference was posted along with a reference to the JACS article on sythesis of lysergic acid methyl ester from L-tryptophan and some article on the synthesis of LSD from LSA using POCl3. I think the post is available for FTP. : I find it interesting that the LSD molecule is so sensitive to substitution. : There aren't many substitutions that will retain activity (just a couple : of types, as compared with the psychedelic phenethylamine family where you : can do just tons of stuff). It must be fitting into that receptor pocket : really nicely. Especially the diethylamine group. I understand just : about any other substitution pattern there pretty much abolishes activity. : Hmm. I wonder if you replaced some of the -H's on those two ethyl groups : with -F's... That would keep the size about the same, but would change the : charge distribution. Has it been tried? -F for -H is supposed to be a : fun substitution in bioactive molecules, often modifying activity since : it's the same size (roughly) as -H, but is a lot harder for enzymes to : take off. Apparently monofluoroacetic acid is one of the most generally : toxic substances known (i.e. bad for most life forms) because it gets into : some important pathway (related to carbon oxidation, Kreb's cycle?) and : totally fucks it all to hell. There are other LS amides that _are_ active at dosages less than 20x that of LSD including ALD-52, d-LS morpholide (20% LSD activity), 1-N-methyl LSD (40% activity), d-LS dimethylamide (10%), d-LS ethylamide (5%) and d-(1-N-methyl-LS-pyrrolidide) (7%) I think research into fluroLSDs has been a bit limited (I certainly havent seen any in my wandering, and it being a fairly notorious sheduled drug must put a bit of a damper on human trials..) It is, however, a good idea.. Does anyone have information on the breakdown path of LSD, I think it is metabolised by MAO. Certainly MAOIs increase LSD potency. : Also, -Cl lies somewhere between -H and -CH3 in size (or so I'm told) so : making of the ethyl groups a 2-chloroethyl group wouldn't be quite as : bad size-wise as making it a propyl group (which apparently abolishes : activity). Of course, 2-chloroethyl ethyl amine would polymerize/cyclize : nicely. Maybe it wouldn't be too easy to work with, so a different sure looks that way.. : synthesis might be required rather than just using a different amine in : the amidation step. But I don't really know what I'm talking about, I'm : just throwing out ideas. you and me both :) : ------------------------------------------------------------------------------ : FIRST CHURCH OF CHRIS ORGANIC CHEMIST : Waterloo, Ont. : Better living through chemistry -- For every problem, a chemical solution. : ------------------------------------------------------------------------------ Sam