Methylene shuffle

Example of the methylene shuffle: LSD and MiPLA

LSD
MiPLA

The methylene shuffle is a strategy in medicinal chemistry used to modify the hydrophobicity of a compound.^[1]^[2]^[3] It involves shortening one alkyl chain by one carbon unit and lengthening another alkyl chain by one carbon unit.^[1]^[2]

An example of the methylene shuffle is the structural modification of the psychedelic drug lysergic acid diethylamide (LSD), which has N,N-diethyl groups, into methylisopropyllysergamide (MiPLA), which has N-methyl and N-isopropyl groups.^[4]^[5]^[6]

References

^ a b Patrick, G.L. (2017). An Introduction to Medicinal Chemistry. Oxford University Press. p. 835. ISBN 978-0-19-874969-1. Retrieved 22 October 2025. Methylene shuffle: A strategy used to alter the hydrophobicity of a molecule. One alkyl chain is shortened by one carbon unit, while another is lengthened a one carbon unit.
^ a b Kumar, T. Durai Ananda (1 June 2022). Drug Design: A Conceptual Overview. CRC Press. ISBN 978-1-000-60388-0. Retrieved 22 October 2025. MOLECULAR MODIFICATION: Homologation: A process of increasing the molecular chain length of molecule by a constant unit (e.g., methylene). The increase or decrease in the alkyl group size (methylene shuffle strategy) influences the therapeutic potential. The molecular modification either increases or decreases the biological activity of molecules. The increase in carbon length in turn increases the molecular lipophilicity (membrane penetration) and the bioavailability. This offers enhanced therapeutic effect. The carbon chain length beyond certain level disturbs the optimal balance between lipophilicity and hydrophilicity The imbalance in molecular properties decreases the bioavailability and therapeutic activity, (e.g., local anaesthetics).
^ Wood, A. (2006). Annual Reports in Medicinal Chemistry. Annual Reports in Medicinal Chemistry. Academic Press. p. 433. ISBN 978-0-08-046741-2. Retrieved 22 October 2025. Common tactics employed by the experienced medicinal chemist include "methylene shuffle", adding lipophilicity, adding chirality, searching for hydrogen-bond interactions, introducing or breaking conformational constraints, amongst many others [76].
^ 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.
^ Huang X, Marona-Lewicka D, Pfaff RC, Nichols DE (March 1994). "Drug discrimination and receptor binding studies of N-isopropyl lysergamide derivatives". Pharmacology Biochemistry and Behavior. 47 (3): 667–673. doi:10.1016/0091-3057(94)90172-4. PMID 8208787. S2CID 16490010.
^ Halberstadt AL, Klein LM, Chatha M, Valenzuela LB, Stratford A, Wallach J, Nichols DE, Brandt SD (February 2019). "Pharmacological characterization of the LSD analog N-ethyl-N-cyclopropyl lysergamide (ECPLA)". Psychopharmacology (Berl). 236 (2): 799–808. doi:10.1007/s00213-018-5055-9. PMC 6848745. PMID 30298278.

[Patrick2017-1] Patrick, G.L. (2017). An Introduction to Medicinal Chemistry. Oxford University Press. p. 835. ISBN 978-0-19-874969-1. Retrieved 22 October 2025. Methylene shuffle: A strategy used to alter the hydrophobicity of a molecule. One alkyl chain is shortened by one carbon unit, while another is lengthened a one carbon unit.

[Kumar2022-2] Kumar, T. Durai Ananda (1 June 2022). Drug Design: A Conceptual Overview. CRC Press. ISBN 978-1-000-60388-0. Retrieved 22 October 2025. MOLECULAR MODIFICATION: Homologation: A process of increasing the molecular chain length of molecule by a constant unit (e.g., methylene). The increase or decrease in the alkyl group size (methylene shuffle strategy) influences the therapeutic potential. The molecular modification either increases or decreases the biological activity of molecules. The increase in carbon length in turn increases the molecular lipophilicity (membrane penetration) and the bioavailability. This offers enhanced therapeutic effect. The carbon chain length beyond certain level disturbs the optimal balance between lipophilicity and hydrophilicity The imbalance in molecular properties decreases the bioavailability and therapeutic activity, (e.g., local anaesthetics).

[Wood2006-3] Wood, A. (2006). Annual Reports in Medicinal Chemistry. Annual Reports in Medicinal Chemistry. Academic Press. p. 433. ISBN 978-0-08-046741-2. Retrieved 22 October 2025. Common tactics employed by the experienced medicinal chemist include "methylene shuffle", adding lipophilicity, adding chirality, searching for hydrogen-bond interactions, introducing or breaking conformational constraints, amongst many others [76].

[Nichols2018-4] 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.

[HuangMarona-LewickaPfaff1994-5] Huang X, Marona-Lewicka D, Pfaff RC, Nichols DE (March 1994). "Drug discrimination and receptor binding studies of N-isopropyl lysergamide derivatives". Pharmacology Biochemistry and Behavior. 47 (3): 667–673. doi:10.1016/0091-3057(94)90172-4. PMID 8208787. S2CID 16490010.

[HalberstadtKleinChatha2019-6] Halberstadt AL, Klein LM, Chatha M, Valenzuela LB, Stratford A, Wallach J, Nichols DE, Brandt SD (February 2019). "Pharmacological characterization of the LSD analog N-ethyl-N-cyclopropyl lysergamide (ECPLA)". Psychopharmacology (Berl). 236 (2): 799–808. doi:10.1007/s00213-018-5055-9. PMC 6848745. PMID 30298278.