DOM-CR

DOM-CR
Clinical data
Other names	DOM/CR; "DOM-Conformationally Restrained"; 5,8-Dimethoxy-7-methyl-THIQ; DOM-THIQ; DOM/THIQ
Identifiers
	IUPAC name 5,8-dimethoxy-7-methyl-1,2,3,4-tetrahydroisoquinoline;
CAS Number	228997-46-4;
PubChem CID	10198181;
ChemSpider	8373681;
Chemical and physical data
Formula	C12H17NO2
Molar mass	207.273 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CC1=CC(=C2CCNCC2=C1OC)OC;
	InChI InChI=1S/C12H17NO2/c1-8-6-11(14-2)9-4-5-13-7-10(9)12(8)15-3/h6,13H,4-5,7H2,1-3H3; Key:LDSXYNSFNYUAHP-UHFFFAOYSA-N;

DOM-CR, or DOM/CR, an acronym of "DOM-conformationally restrained", is a tetrahydroisoquinoline (THIQ) and cyclized phenethylamine related to the psychedelics DOM and 2C-D.^[1]^[2]^[3] It is a cyclized THIQ analogue of DOM and 2C-D.^[1]^[2]^[3]

DOM-CR shows more than 20-fold reduced affinity for the serotonin 5-HT_2A receptor compared to DOM (K_i = 2,150 nM vs. 100 nM, respectively).^[3] In contrast to DOM, DOM-CR does not substitute for DOM in rodent drug discrimination tests, suggesting that it lacks psychedelic effects.^[1]^[2]^[3] Similarly, DOM-CR does not substitute for dextroamphetamine or MDMA, suggesting that it likewise lacks stimulant or entactogenic effects.^[2] However, DOM-CR does substitute for TDIQ (MDTHIQ), a selective α₂-adrenergic receptor ligand.^[1]^[2] At high doses, DOM-CR produces behavioral disruption in drug discrimination tests.^[2] In contrast to DOM and amphetamine, DOM-CR does not produce hyperlocomotion in rodents.^[3]

DOM-CR was first described in the scientific literature by Richard Glennon and colleagues by 1996.^[2]^[3]

Analogues

Other cyclized THIQ analogues of psychoactive phenethylamines have also been developed and characterized.^[2]^[3]^[4]^[5]^[6] These include AMPH-CR (THIQ), METH-CR (N-methyl-THIQ), TDIQ (MDTHIQ, MDA-CR), TDMIQ (MDMTHIQ, MDMA-CR), N-methyl-DOM-CR (Beatrice-CR), DOB-CR, and PMMA-CR.^[2]^[3]^[4]^[5]^[6] Conformational restriction of stimulant, hallucinogen, and/or entactogen phenethylamines into THIQ analogues, like the preceding compounds, usually reduces or abolishes their associated effects as well as their affinities for monoamine transporters and/or serotonin 5-HT₂ receptors.^[2]^[4] However, it does not necessarily remove all pharmacological activity, as evidenced by some THIQs interacting with α₂-adrenergic receptors^[2] as well as serotonin 5-HT_1D, 5-HT₆, and/or 5-HT₇ receptors^[2]^[7]^[8] and producing behavioral effects in animals.^[2]

Other cyclized analogues of DOM and related psychedelics include DOM-AT, DOM-AI, DMCPA, TFMBOX, jimscaline, TCB-2, LPH-5, and ZC-B.^[9]^[10]^[11]

References

^ ^a ^b ^c ^d Glennon RA, Young R (5 August 2011). "Role of Stereochemistry in Drug Discrimination Studies". Drug Discrimination. Wiley. pp. 129–161. doi:10.1002/9781118023150.ch4. ISBN 978-0-470-43352-2. Retrieved 22 May 2025. Figure 4-13. Chemical structures of TDIQ, and conformationally constrained forms of amphetamine (AMPH-CR), methamphetamine (METH-CR), and the hallucinogens DOM (DOM-CR) and DOB (DOB-CR). [...] Conformationally constrained analogs of the hallucinogens DOM and DOB (i.e., DOM-CR and DOB-CR) were not recognized by rats trained to discriminate 1.0 mg/kg of DOM from saline vehicle, but substituted in rats trained to discriminate TDIQ from vehicle (ED50 = 4.2 and 3.4 mg/kg, respectively) [15]. Interestingly, the TDIQ stimulus did not generalize to the N-methyl analog of DOM-CR [15]. Taken together with the findings obtained for METH-CR, it would appear that N-methylation is not tolerated with regard to producing TDIQ-like discriminative stimulus effects [15]. But, more importantly, and to reiterate what was stated above, it should not be assumed that "inactive" conformationally constrained rotamers are necessarily pharmacologically inactive; results depend on the similarity in the stimulus properties of the training drug and test agent.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m Glennon RA, Young R, Rangisetty JB (May 2002). "Further characterization of the stimulus properties of 5,6,7,8-tetrahydro-1,3-dioxolo[4,5-g]isoquinoline". Pharmacol Biochem Behav. 72 (1–2): 379–387. doi:10.1016/s0091-3057(01)00768-7. PMID 11900809.
^ ^a ^b ^c ^d ^e ^f ^g ^h Malmusi L, Dukat M, Young R, Teitler M, Darmani NA, Ahmad B, Smith C, Glennon RA (January 1996). "1,2,3,4-Tetrahydroisoquinoline analogs of phenylalkylamine stimulants and hallucinogens". Medicinal Chemistry Research. 6 (6): 400–411. Conformationally constrained, 1,2,3,4-tetrahydroisoquinoline (TIQ) analogs of central stimulant (e.g. amphetamine) and hallucinogenic (e.g. DOM) phenylalkylamines were prepared and evaluated to determine the contribution to activity of this conformational restriction. The amphetamine-related TIQs failed to produce locomotor stimulation in mice and did not produce amphetamine-appropriate responding in tests of stimulus generalization in (+)amphetamine-trained rats. Hallucinogen-related TIQs lacked appreciable affinity for 5-HT2A serotonin receptors and did not produce DOM-like effects in tests of stimulus generalization in DOM-trained rats. It is concluded that the phenylalkylamine conformation represented by the TIQs is not a major contributor to these actions.
^ ^a ^b ^c Malmusi L, Dukat M, Young R, Teitler M, Darmani NA, Ahmad B, Smith C, Glennon RA (June 1996). "1,2,3,4-Tetrahydroisoquinoline and related analogs of the phenylalkylamine designer drug MDMA". Medicinal Chemistry Research. 6 (6): 412–426. 1,2,3,4-Tetrahydroisoquinoline (TIQ) analogs of 1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDA) and its N-methyl derivative, MDMA, similar in structure to a TIQ metabolite of MDA, were prepared and examined (a) in tests of central stimulant activity in mice, (b) for their ability to bind at human 5-HT2A receptors, and (c) in tests of stimulus generalization in rats trained to discriminate MDMA from vehicle. In general, the TIQ analogs failed to display appreciable activity in any assay system. Conversely, certain 2-aminotetralin and 2-aminoindan analogs were active in the stimulus generalization studies. It is concluded that TIQ-like conformations do not account for the actions typically associated with MDA- and MDMA-related agents.
^ ^a ^b Young R, Glennon RA (2002). "The stimulus effect of 5,6,7,8-tetrahydro-1,3-dioxolo[4,5-g]isoquinoline is similar to that of cocaine but different from that of amphetamine". Pharmacol Biochem Behav. 71 (1–2): 205–213. doi:10.1016/s0091-3057(01)00666-9. PMID 11812524.
^ ^a ^b Young R (2007). "TDIQ (5,6,7,8-tetrahydro-1,3-dioxolo [4,5-g]isoquinoline): discovery, pharmacological effects, and therapeutic potential". CNS Drug Rev. 13 (4): 405–422. doi:10.1111/j.1527-3458.2007.00022.x. PMC 6494129. PMID 18078426.
^ Poulie CB, Chan CB, Parka A, Lettorp M, Vos J, Raaschou A, Pottie E, Bundgaard MS, Sørensen LM, Cecchi CR, Märcher-Rørsted E, Bach A, Herth MM, Decker A, Jensen AA, Elfving B, Kretschmann AC, Stove CP, Kohlmeier KA, Cornett C, Janfelt C, Kornum BR, Kristensen JL (October 2023). "In Vitro and In Vivo Evaluation of Pellotine: A Hypnotic Lophophora Alkaloid". ACS Pharmacol Transl Sci. 6 (10): 1492–1507. doi:10.1021/acsptsci.3c00142. PMC 10580395. PMID 37854625.
^ Chan CB, Pottie E, Simon IA, Rossebø AG, Herth MM, Harpsøe K, Kristensen JL, Stove CP, Poulie CB (February 2025). "Synthesis, Pharmacological Characterization, and Binding Mode Analysis of 8-Hydroxy-Tetrahydroisoquinolines as 5-HT7 Receptor Inverse Agonists". ACS Chem Neurosci. 16 (3): 439–451. doi:10.1021/acschemneuro.4c00667. PMID 39836645.
^ 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.
^ Monte AP (August 1995). Structure-activity relationships of hallucinogens: Design, synthesis, and pharmacological evaluation of a series of conformationally restricted phenethylamines (Ph.D. thesis). Purdue University. Retrieved 15 April 2025.
^ Nichols DE, Weintraub HJ, Pfister WR, Yim GK (1978). "The use of rigid analogues to probe hallucinogen receptors" (PDF). NIDA Res Monogr (22): 70–83. PMID 101889. Archived from the original (PDF) on August 5, 2023.

External links

DOM-CR - Isomer Design

[GlennonYoung2011-1] Glennon RA, Young R (5 August 2011). "Role of Stereochemistry in Drug Discrimination Studies". Drug Discrimination. Wiley. pp. 129–161. doi:10.1002/9781118023150.ch4. ISBN 978-0-470-43352-2. Retrieved 22 May 2025. Figure 4-13. Chemical structures of TDIQ, and conformationally constrained forms of amphetamine (AMPH-CR), methamphetamine (METH-CR), and the hallucinogens DOM (DOM-CR) and DOB (DOB-CR). [...] Conformationally constrained analogs of the hallucinogens DOM and DOB (i.e., DOM-CR and DOB-CR) were not recognized by rats trained to discriminate 1.0 mg/kg of DOM from saline vehicle, but substituted in rats trained to discriminate TDIQ from vehicle (ED50 = 4.2 and 3.4 mg/kg, respectively) [15]. Interestingly, the TDIQ stimulus did not generalize to the N-methyl analog of DOM-CR [15]. Taken together with the findings obtained for METH-CR, it would appear that N-methylation is not tolerated with regard to producing TDIQ-like discriminative stimulus effects [15]. But, more importantly, and to reiterate what was stated above, it should not be assumed that "inactive" conformationally constrained rotamers are necessarily pharmacologically inactive; results depend on the similarity in the stimulus properties of the training drug and test agent.

[GlennonYoungRangisetty2002-2] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m Glennon RA, Young R, Rangisetty JB (May 2002). "Further characterization of the stimulus properties of 5,6,7,8-tetrahydro-1,3-dioxolo[4,5-g]isoquinoline". Pharmacol Biochem Behav. 72 (1–2): 379–387. doi:10.1016/s0091-3057(01)00768-7. PMID 11900809.

[MalmusiDukatYoung1996a-3] ^ ^a ^b ^c ^d ^e ^f ^g ^h Malmusi L, Dukat M, Young R, Teitler M, Darmani NA, Ahmad B, Smith C, Glennon RA (January 1996). "1,2,3,4-Tetrahydroisoquinoline analogs of phenylalkylamine stimulants and hallucinogens". Medicinal Chemistry Research. 6 (6): 400–411. Conformationally constrained, 1,2,3,4-tetrahydroisoquinoline (TIQ) analogs of central stimulant (e.g. amphetamine) and hallucinogenic (e.g. DOM) phenylalkylamines were prepared and evaluated to determine the contribution to activity of this conformational restriction. The amphetamine-related TIQs failed to produce locomotor stimulation in mice and did not produce amphetamine-appropriate responding in tests of stimulus generalization in (+)amphetamine-trained rats. Hallucinogen-related TIQs lacked appreciable affinity for 5-HT2A serotonin receptors and did not produce DOM-like effects in tests of stimulus generalization in DOM-trained rats. It is concluded that the phenylalkylamine conformation represented by the TIQs is not a major contributor to these actions.

[MalmusiDukatYoung1996b-4] Malmusi L, Dukat M, Young R, Teitler M, Darmani NA, Ahmad B, Smith C, Glennon RA (June 1996). "1,2,3,4-Tetrahydroisoquinoline and related analogs of the phenylalkylamine designer drug MDMA". Medicinal Chemistry Research. 6 (6): 412–426. 1,2,3,4-Tetrahydroisoquinoline (TIQ) analogs of 1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDA) and its N-methyl derivative, MDMA, similar in structure to a TIQ metabolite of MDA, were prepared and examined (a) in tests of central stimulant activity in mice, (b) for their ability to bind at human 5-HT2A receptors, and (c) in tests of stimulus generalization in rats trained to discriminate MDMA from vehicle. In general, the TIQ analogs failed to display appreciable activity in any assay system. Conversely, certain 2-aminotetralin and 2-aminoindan analogs were active in the stimulus generalization studies. It is concluded that TIQ-like conformations do not account for the actions typically associated with MDA- and MDMA-related agents.

[YoungGlennon2002-5] Young R, Glennon RA (2002). "The stimulus effect of 5,6,7,8-tetrahydro-1,3-dioxolo[4,5-g]isoquinoline is similar to that of cocaine but different from that of amphetamine". Pharmacol Biochem Behav. 71 (1–2): 205–213. doi:10.1016/s0091-3057(01)00666-9. PMID 11812524.

[Young2007-6] Young R (2007). "TDIQ (5,6,7,8-tetrahydro-1,3-dioxolo [4,5-g]isoquinoline): discovery, pharmacological effects, and therapeutic potential". CNS Drug Rev. 13 (4): 405–422. doi:10.1111/j.1527-3458.2007.00022.x. PMC 6494129. PMID 18078426.

[PoulieChanParka2023-7] Poulie CB, Chan CB, Parka A, Lettorp M, Vos J, Raaschou A, Pottie E, Bundgaard MS, Sørensen LM, Cecchi CR, Märcher-Rørsted E, Bach A, Herth MM, Decker A, Jensen AA, Elfving B, Kretschmann AC, Stove CP, Kohlmeier KA, Cornett C, Janfelt C, Kornum BR, Kristensen JL (October 2023). "In Vitro and In Vivo Evaluation of Pellotine: A Hypnotic Lophophora Alkaloid". ACS Pharmacol Transl Sci. 6 (10): 1492–1507. doi:10.1021/acsptsci.3c00142. PMC 10580395. PMID 37854625.

[ChanPottieSimon2025-8] Chan CB, Pottie E, Simon IA, Rossebø AG, Herth MM, Harpsøe K, Kristensen JL, Stove CP, Poulie CB (February 2025). "Synthesis, Pharmacological Characterization, and Binding Mode Analysis of 8-Hydroxy-Tetrahydroisoquinolines as 5-HT7 Receptor Inverse Agonists". ACS Chem Neurosci. 16 (3): 439–451. doi:10.1021/acschemneuro.4c00667. PMID 39836645.

[Nichols2018-9] 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.

[Monte1995-10] Monte AP (August 1995). Structure-activity relationships of hallucinogens: Design, synthesis, and pharmacological evaluation of a series of conformationally restricted phenethylamines (Ph.D. thesis). Purdue University. Retrieved 15 April 2025.

[NicholsWeintraubPfister1978-11] Nichols DE, Weintraub HJ, Pfister WR, Yim GK (1978). "The use of rigid analogues to probe hallucinogen receptors" (PDF). NIDA Res Monogr (22): 70–83. PMID 101889. Archived from the original (PDF) on August 5, 2023.

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DOM-CR

Analogues

See also

References

External links

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