2-Iodo-LSD

2-Iodo-LSD
Clinical data
Other names	Iodo-LSD; Iodine-LSD; IOL; 2-Iodolysergic acid diethylamide; 2-Iodo-N,N-diethyllysergamide; N,N-Diethyl-2-iodo-6-methyl-9,10-didehydroergoline-8β-carboxamide
Drug class	Serotonin receptor modulator; Non-hallucinogenic serotonin 5-HT2A receptor modulator
ATC code	None;
Identifiers
	IUPAC name (6aR,9R)-N,N-diethyl-5-iodo-7-methyl-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide;
CAS Number	3712-25-2;
PubChem CID	151142;
ChemSpider	133214;
ChEMBL	ChEMBL433352;
CompTox Dashboard (EPA)	DTXSID30958287 ;
Chemical and physical data
Formula	C20H24IN3O
Molar mass	449.336 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CCN(CC)C(=O)[C@H]1CN([C@@H]2CC3=C(NC4=CC=CC(=C34)C2=C1)I)C;
	InChI InChI=1S/C20H24IN3O/c1-4-24(5-2)20(25)12-9-14-13-7-6-8-16-18(13)15(19(21)22-16)10-17(14)23(3)11-12/h6-9,12,17,22H,4-5,10-11H2,1-3H3/t12-,17-/m1/s1; Key:OBCUQRYIGTWROI-SJKOYZFVSA-N;

2-Iodo-LSD (IOL) is a putatively non-hallucinogenic serotonin receptor modulator of the lysergamide family related to 2-bromo-LSD (BOL-148) and lysergic acid diethylamide (LSD).^[1]^[2]^[3] It is the 2-iodo derivative of LSD.^[1]^[2]^[3]

Pharmacology

The drug shows high affinity for the serotonin 5-HT₂ receptors and also shows affinity for other serotonin receptors as well as for the dopamine and adrenergic receptors.^[4]^[5] In contrast to LSD, but similarly to 2-bromo-LSD, 2-iodo-LSD is predominantly antagonistic at the serotonin 5-HT_2A and 5-HT_2C receptors and is described as non-hallucinogenic.^[1]^[2]^[3]^[6] The drug has about 57.4% of the antiserotonergic activity of LSD in the isolated rat uterus in vitro, whereas 2-bromo-LSD has about 103% of LSD's potency in this assay.^[7]^[8]^[9]

Radiolabeling

[¹²⁵I]2-Iodo-LSD, a radiolabeled analogue of 2-iodo-LSD, has been used as a radioligand for serotonin 5-HT₂ receptors.^[1]^[2]^[10] In addition, radiolabeled derivatives of 2-iodo-LSD, such as 1-methyl-2-[¹²⁵I]iodo-LSD ([¹²⁵I]-MIL) and 1-ethyl-2-[¹²⁵I]iodo-LSD ([¹²⁵I]-EIL), have been developed for use as presumably non-hallucinogenic agents in imaging of serotonin receptors.^[11]^[12]

History

2-Iodo-LSD was described in the scientific literature by Albert Hofmann and colleagues by 1956.^[13]^[14]^[8]^[7]

References

^ ^a ^b ^c ^d Nichols DE (2018). "Chemistry and Structure-Activity Relationships of Psychedelics". Current Topics in Behavioral Neurosciences. Vol. 36. pp. 1–43. doi:10.1007/7854_2017_475. ISBN 978-3-662-55878-2. PMID 28401524. If a halogen is introduced at the 2-position of LSD, for example in 2-bromo-LSD (BOL-148) or 2-iodo-LSD, the resulting molecules lack hallucinogenic activity and are antagonists at the 5-HT2A receptor. No work with BOL-148 has been reported since the early 1970s, but it was shown that it could block the effects of LSD in humans.(Ginzel and Mayer-Gross 1956) The radiolabeled 2-iodo congener, [125I] 2-iodo-LSD, has been employed as a radioligand for 5-HT2 family receptors (Hartig et al. 1983; Nakada et al. 1984; McKenna et al. 1989; Watts et al. 1994). More recently, BOL has shown efficacy in aborting and/or preventing cluster headaches (Karst et al. 2010).
^ ^a ^b ^c ^d Nichols DE (2012). "Structure–activity relationships of serotonin 5-HT 2A agonists" (PDF). Wiley Interdisciplinary Reviews: Membrane Transport and Signaling. 1 (5): 559–579. doi:10.1002/wmts.42. ISSN 2190-460X. Halogenation at the 2-position of LSD as in 2-bromo-LSD (BOL-148) or 2-iodo-LSD leads to molecules that are 5-HT2A antagonists. Although virtually no work has been done with BOL-148 since the early 1970s, it was demonstrated early on that it could block the effects of LSD in humans.26 [125I]2-Iodo-LSD has found application as a radioactive label for 5-HT2 family receptors.27–30
^ ^a ^b ^c Halberstadt AL, Geyer MA (2013). "[Chapter 61:] Neuropharmacology of Lysergic Acid Diethylamide (LSD) and Other Hallucinogens". In Miller PM, Blume AW, Kavanagh DJ, Kampman KM, Bates ME, Larimer ME, Petry NM, De Witte P, Ball SA (eds.). Biological Research on Addiction: Comprehensive Addictive Behaviors and Disorders. Vol. 2. Elsevier. pp. 625–635. doi:10.1016/b978-0-12-398335-0.00061-3. ISBN 978-0-12-398335-0. Archived from the original on 28 March 2025. There is a complete loss of activity if LSD is brominated or iodinated in the 2-position, and these substances (2-bromo-LSD and 2-iodo-LSD, respectively) act as 5-HT2A antagonists. Consistent with its antagonist activity, pretreatment with 2-bromo-LSD completely blocks the effects of subsequent LSD administration.
^ Glennon RA (July 2003). "Higher-end serotonin receptors: 5-HT(5), 5-HT(6), and 5-HT(7)". Journal of Medicinal Chemistry. 46 (14): 2795–2812. doi:10.1021/jm030030n. PMID 12825922.
^ Middlemiss DN, Hibert M, Fozard JR (1986). "Chapter 5. Drugs Acting at Central 5-Hydroxytryptamine Receptors". Annual Reports in Medicinal Chemistry. Vol. 21. Elsevier. pp. 41–50. doi:10.1016/s0065-7743(08)61115-x. ISBN 978-0-12-040521-3. Retrieved 30 June 2025.
^ Glennon RA, Dukat M (December 1991). "Serotonin receptors and their ligands: a lack of selective agents". Pharmacology, Biochemistry, and Behavior. 40 (4): 1009–1017. doi:10.1016/0091-3057(91)90121-h. PMID 1816555.
^ ^a ^b Cerletti A, Doepfner W (January 1958). "Comparative study on the serotonin antagonism of amide derivatives of lysergic acid and of ergot alkaloids". The Journal of Pharmacology and Experimental Therapeutics. 122 (1): 124–136. doi:10.1016/S0022-3565(25)11933-2. PMID 13502837.
^ ^a ^b Rothlin E (March 1957). "Lysergic acid diethylamide and related substances". Annals of the New York Academy of Sciences. 66 (3): 668–676. Bibcode:1957NYASA..66..668R. doi:10.1111/j.1749-6632.1957.tb40756.x. PMID 13425249.
^ Hintzen A, Passie T (10 June 2010). The Pharmacology of LSD. OUP/Beckley Foundation Press. p. 19. ISBN 978-0-19-958982-1. Retrieved 30 June 2025. 2-Bromo-lysergic acid diethylamide (BOL-148) The most investigated lysergic acid derivative after LSD is bromo-LSD (BOL-148) (Table 2.3). Whilst the strength of serotonin antagonism with LSD is comparable, it possesses almost no psychic effects (even in doses up to 20 μg/kg). The only psychic effect described was a feeling of tiredness and some psychophysical irritation at high doses (Cerletti & Konzett, 1956). [...] Iodine-LSD is iodinated in position 2 and is only half as effective in relation to psychic effects, as well as to serotonin antagonism, as LSD itself (Cerletti & Konzett, 1956). [...]
^ Engel G, Müller-Schweinitzer E, Palacios JM (April 1984). "2-[125Iodo]LSD, a new ligand for the characterisation and localisation of 5-HT2 receptors". Naunyn-Schmiedeberg's Archives of Pharmacology. 325 (4): 328–336. doi:10.1007/BF00504377. PMID 6728042.
^ Cumming P, Scheidegger M, Dornbierer D, Palner M, Quednow BB, Martin-Soelch C (April 2021). "Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans". Molecules. 26 (9). Basel, Switzerland: 2451. doi:10.3390/molecules26092451. PMC 8122807. PMID 33922330. N-methyl-2-[125I]-iodo-lysergic acid diethylamide ([125I]-MIL, 24) was developed as a presumably non-hallucinogenic ligand for the molecular imaging of serotonin receptors, whereby N-methylation of [125I]-LSD (25) was intended to impart greater selectivity and sensitivity for 5HT2 receptors [23]. [...] D-(+)-N-ethyl-2-[125I]iodo-lysergic acid diethylamide ([125I]-EIL, 23) was developed as a ligand for molecular imaging of serotonin receptors. [...]
^ Shulgin AT (2003). "Basic Pharmacology and Effects". In Laing RR (ed.). Hallucinogens: A Forensic Drug Handbook. Forensic Drug Handbook Series. Elsevier Science. pp. 67–137. ISBN 978-0-12-433951-4.
^ Troxler F, Hofmann A (1957). "Substitutionen am Ringsystem der Lysergsäure. III. Halogenierung. 45. Mitteilung über Mutterkornalkaloide". Helvetica Chimica Acta. 40 (7): 2160–2170. Bibcode:1957HChAc..40.2160T. doi:10.1002/hlca.19570400716. ISSN 0018-019X. Retrieved 30 June 2025.
^ Cerletti A, Konzett H (1956). "Spezifische Hemmung von 5-Oxytryptamin-Effekten durch Lysergsäurediäthylamid und ähnliche Körper" [Specific inhibition of serotonin effects by lysergic acid diethylamide and similar compounds]. Naunyn-Schmiedebergs Archiv für Experimentelle Pathologie und Pharmakologie (in German). 228 (1–2): 146–148. doi:10.1007/BF00259761. PMID 13334586. Substitutionsprodukte des LSD 1. Acetyl-LSD, durch Einfiihrung eines Acetylrestes in 1-Stellung gewonnen, ist etwa 2mal starker 50T-hemmend wirksam. Brom- und Jod-LSD, durch Einffihrung von Brom und Jod in 2-Stellung bereitet, sind 1,5mal starker bzw. 2real schw~cher 50T-hemmend wirksam. Oxymethyl-LSD, durch Einffihrung einer 0xymethylgruppe in 1-Stellung gewonnen, ist 1,5mal schw~icher wirksam.