Analytical and Pharmacological Characterization of 1‐(Furan‐2‐Carbonyl)‐LSD (1F‐LSD) and Comparison With 1‐(Thiophene‐2‐Carbonyl)‐LSD (1T‐LSD)

ABSTRACT The classical psychedelic drug (+)‐lysergic acid diethylamide (LSD) continues to attract considerable multidisciplinary interest, and over the last eight decades, many derivatives and analogs of LSD have been synthesized. One site on the ergoline scaffold of LSD that has been frequently modified is the N1‐position, with the N1‐acylated LSD derivative 1‐acetyl‐LSD (1A‐LSD, ALD‐52) being one of the earliest examples. In more recent years, several other alkylcarbonyl‐ and cycloalkylcarbonyl‐substituted LSD derivatives have been evaluated, including several distributed as research chemicals. Although N1‐substitution is detrimental for the activity of LSD at the 5‐HT2A receptor (the primary site of action of psychedelic drugs), N1‐acylated LSD derivatives are rapidly hydrolyzed in vivo and are believed to act as prodrugs for LSD. Recently, 1‐(thiophene‐2‐carbonyl)‐LSD (1T‐LSD, SYN‐L‐021) was detected as a new recreational drug, signaling a move towards N1‐acyl groups with an aromatic character. The present study was conducted to investigate the analytical profile and pharmacology of 1‐(2‐furoyl)‐lysergic acid diethylamide (1F‐LSD, SYN‐L‐005), a novel analog of 1T‐LSD. The binding of 1F‐LSD to the 5‐HT2A receptor and other monoamine sites was assessed using radioligand binding. Furthermore, the in vivo activities of 1F‐LSD and 1T‐LSD were assessed in C57BL/6 J mice by comparing their biotransformation to LSD and effects on the head‐twitch response (HTR), a 5‐HT2A‐mediated behavior. Both 1F‐LSD and 1T‐LSD induced the HTR in mice and were hydrolyzed to LSD after in vivo administration, indicating that both substances exhibit LSD‐like properties and may serve as prodrugs for LSD.