2C (psychedelics)

General structure of a 2C compound

2C (2C-x) is a general name for the family of psychedelic phenethylamines containing methoxy groups on the 2 and 5 positions of a benzene ring. ^{[1] [2] [3]} Most of these compounds also carry lipophilic substituents at the 4 position, usually resulting in more potent and more metabolically stable and longer acting compounds. ^[4]

Most of the currently known 2C compounds were first synthesized by Alexander Shulgin in the 1970s and 1980s and published in his book PiHKAL (Phenethylamines i Have Known And Loved). ^[3] Shulgin also coined the term 2C, being an acronym for the 2 carbon atoms between the benzene ring and the amino group. ^{[5] [1] [3]} 2C-B is the most popular of the 2C drugs. ^[3]

Pharmacology

Pharmacodynamics

Actions

The 2C drugs act as agonists of the serotonin 5-HT₂ receptors, including of the serotonin 5-HT_2A, 5-HT_2B, and 5-HT_2C receptors. ^{[6] [7] [8] [9] [10]} They are partial agonists of the serotonin 5-HT_2A receptor. ^{[6] [7]} Most of the 2C drugs have much lower affinity for the serotonin 5-HT_1A receptor than for the serotonin 5-HT_2A receptor. ^{[6] [7] [8] [9]} Most of the 2C drugs have also shown about 5- to 15-fold higher affinity for the serotonin 5-HT_2A receptor over the serotonin 5-HT_2C receptor and about 15- to 100-fold higher affinity for the serotonin 5-HT_2A receptor over the serotonin 5-HT_1A receptor. ^[7] The psychedelic effects of the 2C drugs are thought to be mediated specifically by activation of the serotonin 5-HT_2A receptor. ^{[6] [8] [10]}

Unlike many other phenethylamines, 2C drugs, including 2C-C, 2C-D, 2C-E, 2C-I, and 2C-T-2 among others, are inactive as monoamine releasing agents and reuptake inhibitors. ^{[6] [11] [8] [7] [10]} Most of the 2C drugs are agonists of the rat and mouse trace amine-associated receptor 1 (TAAR1). ^{[6] [12] [13] [7]} However, most are inactive as agonists of the human TAAR1. ^{[6] [12] [13] [7]} The 2C drugs show very weak monoamine oxidase inhibition, including of monoamine oxidase A (MAO-A) and/or monoamine oxidase B (MAO-B). ^[6]

Effects

In accordance with their psychedelic effects in humans, the 2C drugs produce the head-twitch response and wet dog shakes, behavioral proxies of psychedelic effects, in rodents. ^[6] At least some 2C drugs, such as 2C-D and 2C-E, produce hyperlocomotion at lower doses in rodents. ^[6] All 2C drugs produce hypolocomotion at higher doses in rodents. ^[6] 2C drugs, including 2C-C, 2C-D, 2C-E, and 2C-I, substitute partially to fully for psychedelics like DOM, DMT, and LSD and/or for the entactogen MDMA in rodent drug discrimination tests. ^{[6] [8]} However, none of the assessed 2C drugs substituted for dextromethamphetamine, suggesting that they lack amphetamine-type or stimulant-like effects. ^{[6] [8]}

In contrast to most psychedelics, at least two assessed 2C drugs, 2C-C and 2C-P, have shown reinforcing effects in rodents, including conditioned place preference (CPP) and self-administration. ^{[6] [14]} The mechanism by which these effects are mediated is unknown. ^[6] However, it may be related to reduced expression of the dopamine transporter (DAT) and increased DAT phosphorylation, in turn resulting in increased extracellular dopamine levels in certain brain areas. ^{[6] [14]} These 2C drugs might have misuse potential in humans. ^{[6] [14]} Similar reinforcing effects in animals have been observed for NBOMe analogues of 2C drugs, including 25B-NBOMe, 25D-NBOMe, 25E-NBOMe, 25H-NBOMe, and 25N-NBOMe. ^{[6] [15] [16] [17] [18] [19] [20]}

Similarly to DOI, tolerance has been found to gradually develop to the head-twitch response induced by 2C-T-7 with chronic administration in rodents. ^[6]

Pharmacokinetics

The 2C drugs are orally active and most have doses in the range of 10 to 60 mg and durations in the range of 4 to 12 hours. ^[1] They are metabolized by O-demethylation and deamination (by monoamine oxidases). ^[1]

History

See also: DOx § History

2,4,5-Trimethoxyphenethylamine (2,4,5-TMPEA; 2C-O or "2C-MeO") was first synthesized by Jansen and was found to produce psychedelic effects similar to those of mescaline (3,4,5-trimethoxyphenethylamine). ^{[21] [22]} He published his findings in 1931. ^{[21] [22]} However, subsequent studies in the 1960s and 1970s suggested that 2,4,5-TMPEA may actually be inactive as a psychedelic in animals and humans. ^[21]

2C-D (2C-M) was the first of the 2C drugs to be discovered. ^{[23] [24] [25] [26]} It was synthesized and studied in animals by Ho and colleagues and they published their findings in 1970. ^{[23] [24] [25] [26]} Alexander Shulgin synthesized 2C-B and 2C-D in 1974 and discovered their psychedelic effects in self-experiments conducted in 1974 and 1975. ^{[1] [27] [23] [24] [28]} He published his findings in the scientific literature in 1975. ^{[1] [27] [23] [24] [28]} 2C-I was first described by Shulgin and colleagues in 1977 and initial psychoactivity was reported by Shulgin in 1978. ^{[21] [29]} Shulgin also first synthesized 2C-E in 1977. ^{[30] [31]} Subsequently, numerous other 2C drugs have been synthesized and characterized. ^{[5] [32] [23] [1] [27]}

2C-B gained popularity as a recreational drug and MDMA alternative in the mid-1980s and became a controlled substance in the United States in 1994. ^{[1] [3]} It is said to be the most popular of the 2C drugs. ^[3]

List of 2C drugs

Nomenclature	R3	R4	2D Structure	CAS number
2C-B	H	Br		66142-81-2
2C-Bn	H	CH2C6H5
2C-Bu	H	CH2CH2CH2CH3
2C-C	H	Cl		88441-14-9
2C-C-3 [33]	Cl	Cl
2C-CN	H	C≡N		88441-07-0
2C-D	H	CH3		24333-19-5
2C-E	H	CH2CH3		71539-34-9
2C-EF	H	CH2CH2F		1222814-77-8
2C-F	H	F		207740-15-6
2C-G	CH3	CH3		207740-18-9
2C-G-1	CH2
2C-G-2	(CH2)2
2C-G-3	(CH2)3			207740-19-0
2C-G-4	(CH2)4			952006-59-6
2C-G-5	(CH2)5			207740-20-3
2C-G-6	(CH2)6
2C-G-N	(CH)4			207740-21-4
2C-H	H	H		3600-86-0
2C-I	H	I		69587-11-7
2C-iBu	H	iBu
2C-iP	H	CH(CH3)2		1498978-47-4
2C-TBU	H	C(CH3)3
2C-CP	H	C3H5		2888537-46-8
2C-CPE	H	C5H9
2C-N	H	NO2		261789-00-8
2C-NH2	H	NH2		168699-66-9
2C-PYR	H	Pyrrolidine
2C-PIP	H	Piperidine
2C-O	H	OCH3		15394-83-9
2C-O-4	H	OCH(CH3)2		952006-65-4
2C-MOM [34]	H	CH2OCH3
2C-P	H	CH2CH2CH3		207740-22-5
2C-Ph	H	C6H5
2C-Se	H	Se CH3		1189246-68-1
2C-T	H	SCH3		61638-09-3
2C-T-2	H	SCH2CH3		207740-24-7
2C-T-3 [35]	H	SCH2C(=CH2)CH3		648957-40-8
2C-T-4	H	SCH(CH3)2		207740-25-8
2C-T-5 [35]
2C-T-6 [35]
2C-T-7	H	S(CH2)2CH3		207740-26-9
2C-T-8	H	SCH2CH(CH2)2		207740-27-0
2C-T-9 [35]				207740-28-1
2C-T-10 [35]
2C-T-11 [35]
2C-T-12 [35]
2C-T-13	H	S(CH2)2OCH3		207740-30-5
2C-T-14 [35]
2C-T-15	H	SCH(CH2)2
2C-T-16 [36]	H	SCH2CH=CH2		648957-42-0
2C-T-17	H	SCH(CH3)CH2CH3		207740-32-7
2C-T-18 [35]
2C-T-19	H	SCH2CH2CH2CH3
2C-T-21	H	S(CH2)2F		207740-33-8
2C-T-21.5 [35]				648957-46-4
2C-T-22 [35]				648957-48-6
2C-T-23 [35]
2C-T-24 [35]
2C-T-25 [35]
2C-T-27 [35]				648957-52-2
2C-T-28 [35]				648957-54-4
2C-T-30 [35]
2C-T-31 [35]
2C-T-32 [35]
2C-T-33 [35]
2C-T-DFM	H	SCF2H
CYB210010 (2C-T-TFM) [37]	H	SCF3
2C-T-DFP	H	SCH2CH2CF2H
2C-T-PARGY	H	SCH2C≡CH
2C-DFM [38] : 770	H	CHF2
2C-TFM	H	CF3		159277-08-4
2C-TFE	H	CH2CF3
2C-PFE	H	CF2CF3
2C-PFS	H	SF5
2C-YN	H	C≡CH		752982-24-4
2C-V	H	CH=CH2
2C-AL [39]	H	CH2CH=CH2

Legality

Canada

As of October 12, 2016, the 2C-x family of substituted phenethylamines is a controlled substance (Schedule III) in Canada. ^[40]

See also

• 25-NB
• Substituted phenethylamines
• Substituted amphetamines
• Substituted methylenedioxyphenethylamines
• DOx
• Substituted tryptamines
• List of miscellaneous 5-HT2A receptor agonists
• PiHKAL
• The Shulgin Index

References

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