Serotonin Receptors

Serotonin (5-hydroxytryptamine, 5-HT) is widely distributed throughout the mammalian body, being synthesized from L-tryptophan in enterochromaffin cells of the gastro-intestinal tract as well as in serotonergic neurons. The monoamine is a major neurotransmitter in the CNS, but while it is avidly taken up by peripheral sympathetic neurons and co-stored with norepinephrine, evidence for discrete peripheral serotonergic neurons remains equivocal.

In the periphery the primary source of serotonin is the platelets, which sequester serotonin via an active transport mechanism and store it as a serotonin:ATP complex. It is released when platelets aggregate at a site of vascular injury, promoting hemostasis. Serotonin is also released from enterochromaffin cells following exposure to radiation or cancer chemotherapeutic agents such as cisplatin. The ensuing activation of 5-HT₃ receptors on vagal afferents in the gut wall and/or within the area postrema promotes nausea and vomiting. Hence in both of these situations the monoamine stimulates a host organism defense response.

The classification and nomenclature of serotonin receptors is organized according to criteria established by the IUPHAR Subcommittee for the Classification and Nomenclature of Serotonin Receptors. Thirteen distinct human subtypes of serotonin receptor are recognized on the basis of structural, transductional and operational characteristics. A fourteenth putative subtype (5-ht_5B) has been identified in rodents, but not in the human where its coding sequence is interrupted by stop codons. These receptor subtypes fall into seven structurally-defined classes (5-HT₁ to 5-HT₇). However, in a few cases, unambiguous physiological roles have still not been demonstrated hence a lower case appellation is ascribed e.g. 5-ht_1E, 5-ht_1F to distinguish these gene products from receptors with proven operational functionality.

Further structural and operational diversity arises from allelic polymorphism and alternative splicing. For example, seven isoforms of the 5-HT₄ receptor and four isoforms of the human 5-HT₇ receptor are known to be produced by alternative splicing of the receptor mRNA. In addition, up to seven isoforms of the 5-HT_2C receptor, varying in the amino acid composition of the second intracellular loop, have been shown to be produced by editing of the receptor pre-mRNA. All of these isoforms exhibit different tissue distributions, implying tissue-specific functions. While precise roles remain uncertain, these differences may govern rates of receptor desensitization/internalization, intracellular trafficking and the specificity and/or efficiency of coupling to G proteins. One final form of receptor diversity may be represented by receptor homo- and hetero-dimerization. This has been shown for 5-HT_1B and 5-HT_1D receptors in recombinant systems, though its relevance in a native setting has yet to be demonstrated.

In the last 50 years, drugs directly or indirectly targeting serotonin receptors have emerged as an important category of therapeutic agents, providing treatments for a broad range of clinical conditions. Chief among these drugs are selective serotonin reuptake inhibitors (SSRIs) which are widely used in the treatment of depression and various anxiety disorders. By selectively blocking the serotonin transporter, these drugs are thought to work via modulation of 5-HT_1A receptors, a concept reinforced by the proven efficacy of 5-HT_1A receptor agonists, such as buspirone, in the treatment of anxiety. Selective antagonists at 5-HT₃ receptors have transformed cancer therapy by preventing chemotherapy- and radiation-induced vomiting. Likewise, selective 5-HT_1B receptor agonists, exemplified by sumatriptan, zolmitriptan and riztriptan, have established a new standard in the acute treatment of migraine headache. Other 5-HT receptor subtypes being targeted by emerging treatments include: the 5-HT_2A receptor, where antagonists are being sought for the treatment of schizophrenia; the 5-HT_2B receptor, antagonism of which offers promise in both irritable bowel syndrome (IBS) and migraine prophylaxis; the 5-HT_2C receptor, at which selective agonists are pedicted to increase satiety and reduce obesity; the 5-HT₄ receptor, at which antagonists or low efficacy agonists are sought as potential treatments for IBS and finally, the putative 5-ht₆ receptor, selective blockade of which may offer potential in the treatment of cognitive dysfunction.

The Tables below contain accepted modulators and additional information. For a list of additional products, see the Materials section below.

Table 1. Serotonin 5-HT1 Receptors

Currently Accepted Name	5-HT1A	5-HT1Ba	5-HT1Da	5-ht1eb	5-ht1fb
Alternate Name	None	5-HT1Db	5-HT1Da	5-HT1Ea	5-HT1Eb 5-HT6
Structural Information	421 aa (human)	390 aa (human)	377 aa (human)	365 aa (human)	366 aa (human)
Subtype Selective Agonists	R(+)-8-OH-DPAT (H140) U-92016A R(+)-UH-301 (U109)	Sumatriptanc (S1198) Zolmitriptan (SML0248) L-694,247 CGS-12066 (C106)	Sumatriptan (S1198) Zolmitriptan (SML0248) L-694,247	BRL 54443 (B173)	LY-334370 (SML0010) LY-344864 BRL 54443 (B173)
Subtype Selective Antagonists	WAY-100635 (W108) S(–)-UH-301 (U108) NAN-190 (N3529) S(–)-Pindolol (P152) Spiperone (S7395)	GR 55562c (G0419) SB-216641 (S8942) GR 127935 (G5793) SB-224289 (S201)	GR 127935 (G5793) BRL 15572	Not Known	Not Known
Signal Transduction Mechanism	Gi/o (cAMP modulation)	Gi/o (cAMP modulation)	Gi/o (cAMP modulation)	Gi/o (cAMP modulation)	Gi/o (cAMP modulation)
Radioligands of Choice	[3H]-WAY 100635 [3H]-8-OH-DPAT	[3H]-Sumatriptanc [3H]-GR 125743	[3H]-Sumatriptan [3H]-GR 125743	[3H]-5-HT	[3H]-LY-334370 [125I]-I-LSD
Tissue Expression	Hippocampus, amygdala, raphe nuclei, myenteric plexus	Striatum, hippocampus raphe nuclei, sympathetic neurons; vascular smooth muscle	Striatum, hippocampus dorsal raphe, trigeminal ganglion; vascular smooth muscle	Parietal cortex; caudate putamen; olfactory tubercle; amygdala, glial cells	Cortex; thalamus; hippocampus; uterus; mesentery
Physiological Function	Somatodendritic autoreceptor in raphe and hippocampus; somatodendritic heteroreceptor in myenteric plexus	Presynaptic autoreceptor in hippocampus and sympathetic neurons; contraction of smooth muscle	Somatodendritic autoreceptor in raphe and hippocampus; Sympathetic presynaptic autoreceptor	Not Known	Trigeminal neuro inhibition
Disease Relevance	Anxiety disorders	Implicated in aggression; migraine	Potentially migraine	Not Known	Potentially migraine

Footnotes

a) Human receptors now assume primacy in serotonin receptor nomenclature - Trends Pharmacol. Sci., 17, 103-105 (1996). The terms 5-HT1B and 5-HT1D now refer to the human receptors previously termed 5-HT_1Db and 5-HT_1Da, respectively. Non-human orthologs are subsumed within these classes.

b) The use of lower case denotes the identification of a gene product only.

c) Rodent ortholog exhibits different pharmacology: Selective agonist - CP-93,129, selective antagonist - cyanopindolol; radioligand - [¹²⁵I]-iodocyanopindolol.

Abbreviations

BRL 15572: 3-[4-(3-Chlorophenyl)piperazine-1-yl]-1,1-diphenyl-2-propanol
BRL 54443: 3-(1-Methylpiperidin-4-yl)-1H-indol-5-ol
CGS12066: 7-Trifluoromethyl-4-(4-methyl-1-piperazinyl)pyrrolo[1,2-a]quinoxaline
8-OH-DPAT: 8-Hydroxy-2-(di-n-propylamino)tetralin
GR 55562: 3-[3-Dimethylamino)propyl]-4-hydroxy-N-[4-pyridinyl)phenyl]benzamide
GR 125743: N-[4-Methoxy-3-(4-methyl-1-piperizinyl)phenyl]3-methyl-4-(4-pyrindinyl) benzamide
GR 127935: N-[Methoxy-3-(4-methyl-1-piperizinyl)phenyl]-2’-methyl-4’(5-methyl-1,2,4-oxadiazol-3-yl)[1,1-biphenyl]-4-carboxamide
L-694,247: 2-[5-[3-(4-Methylsulphonylamino)benzyl-1,2,4-oxadiazol-5-yl]1H-indol-3-yl]ethanamine
LSD: Lysergic acid diethylamide
LY-334370: 4-Fluoro-N-[3-(1-methyl-4-piperidinyl)-1H-indol-5-yl]-benzamide
LY-344864: (R)-N-[3-Dimethylamino-2,3,4,9-tetrahydro-1H-carbazol-6-yl]-4-fluorobenzamide
NAN-190: 1-(2-Methoxyphenyl)-4-(4-[2-phthalimido]butyl)-piperazine
SB-216641: N-[3-(2-Dimethylamino)ethoxy-4-methoxyphenyl]-2’-methyl-4’-(5-methyl-1,2,4-oxadizaol-3-yl)-(1,1’-biphenyl)-4-carboxamide
SB-224289: 2,3,6,7-Tetrahydro-1'-methyl-5-[2'-methyl-4'(5-methyl-1,2,4-oxadiazo l-3-yl)biphenyl-4-carbonyl]furo[2,3f]indole-3-spiro-4'-piperidine hydrochloride
U-92016A: (+)-R-2-Cyano-N,N-dipropyl-8-amino-6,7,8,9-tetrahydro-3H-benz[e]indole
UH-301: 5-Fluoro-8-hydroxy-2-dipropylamino-1,2,3,4-tetrahydronaphthalene
WAY 100635: N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridyl)-cyclohexanecarboxamide trichloride

Table 2. Serotonin 5-HT2 Receptors

Currently Accepted Name	5-HT2A	5-HT2B	5-HT2C
Alternate Name	D, 5-HT2	5-HT2F	5-HT1C
Structural Information	471 aa (human)	479, 481 aa (human)	458 aa (human)a
Subtype Selective Agonists	α-Me-5-HT (M110) DOI (D101) DOB	α-Me-5-HT (M110) BW 723C86 (B175)	α-Me-5-HT (M110) m-CPP (125180) YM348 Tegaserod (partial)
Subtype Selective Antagonists	Ketanserin (S006) AMI-193 MDL 100,907 R102444	SB-204741 (S0693) SB-200646 SB-206553 (S180) RS-127445 (R2533) EGIS-7625 LY 272015	RS-102221 (R1658) SB-200646 SB-206553 (S180) SB-242084 (S8061)
Signal Transduction Mechanism	Gq/11 (increase IP3/DAG)	Gq/11 (increase IP3/DAG)	Gq/11 (increase IP3/DAG)
Radioligands of Choice	[3H]-Ketanserin	[3H]-5-HT	[3H]-Mesulergine
Tissue Expression	Cortex, hippocampus striatum, vascular and non- vascular smooth muscle blood platelets	Vascular and G-I smooth muscle, stomach fundus, uterus, vascular endothelium	Choroid plexus, striatum, hippocampus, hypothalamus
Physiological Function	Possibly neuro-inhibition, platelet activation, smooth muscle contraction	Smooth muscle contraction NO-dependent vasorelaxation	CSF volume regulation
Disease Relevance	Implicated in schizophrenia	Potentially migraine, anxiety irritable bowel syndrome	Potentially migraine and obesity

Footnote

a) Up to seven functional isoforms are produced by mRNA editing.

Abbreviations

AMI-193: 8-[3-(4-Fluorophenoxy)propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one
BW723C86: 1-[5(2-Thienylmethoxy)-1H-3-indolyl]propan-2-amine hydrochloride
m-CPP: 1-(m-Chlorophenyl)piperazine
DOB: 2,5-Dimethoxy-4-bromoamphetamine
DOI: 1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane
EGIS-7625: (1-Benzyl-4-[(2-nitro-4-methyl-5-amino)-phenyl]-piperazine)
LY272015: 6-Methyl-1,2,3,4-tetrahydro-1-[3,4-dimethoxyphenyl) methyl-9H-pyrido[3,4b]indole] hydrochloride
MDL 100,907: (±)-2,3-Dimethoxyphenyl-1-[2-(4-piperidine)-methanol]
R 102444: (2R,4R)-4-Lauroyloxy-2-[2-[2-[2-(3-methoxy)phenyl]ethyl]phenoxy]ethyl-1-methylpyrrolidine hydrochloride
RS 102221: 8-[5-(5-Amino 2,4-dimethoxyphenyl)-5-oxopentyl]-1,3,8-triazaspiro[4,5]decane-2,4-dione
RS 127445: 2-Amino-4-(4-fluoronapthyl-1-yl)-6-isopropylpyrimidine
SB-200646: N-(1-Methyl-5-indolyl)-N-(3-pyridyl)urea hydrochloride
SB-204741: N-(1-Methyl-5-indolyl)-N-(3-methyl-5-isothiazolyl)urea
SB-242084: 6-Chloro-5-methyl-1-[2-(2-methylpyridyl-3-oxy)-pyrid-5-yl carbamoyl]indoline
SB-206553: N-3-Pyridinyl-3,5-dihydro-5-methyl-benzo(1,2-b:4,5-b’)dipyrrole-1(2H)carboxamide
Tegaserod: 2-[(5-Methoxy-1H-indol-3-yl)methylene]-N-pentylhydrazinecarboximedamide
YM348: S-2-(7-Ethyl-1H-furo[2,3-g]indazol-1-yl)-1-methylethylamine

Table 3. Additional Serotonin Receptor Classes

Currently Accepted Name	5-HT3	5-HT4	5-ht5a,b	5-ht6b	5-HT7 (h) (S177) 5-HT7 (r)
Alternate Name	M	None	5-HT5a 5-HT5b	None	5-HT1-like 5-HTY
Structural Information	478 aa (human)c	387 aa (human [a])d 388 aa (human [b]) 378 aa (human [e])	357 aa (human)e	440 aa (human)	445 aa (human [a])d 432 aa (human [b]) 479 aa (human [d])
Subtype Selective Agonists	SR 57227A (S1688) 2-Methyl-5-HT 1-(m-Chlorophenyl-biguanide (C144) 5-HTQ (H133)	BIMU8 (B4063) RS 67506 ML 10302 (M7319) SC-53116 (PZ0146)	LSD (L7007)	LSD (L7007) 5-CT (C117)	5-CT (C117)
Subtype Selective Antagonists	Granisetron (G3796) Ondansetron (O3639) Tropisetron (T104)	GR 113808 (G5918) SB-204070 (S3313) RS 100235	Not Known	Ro 04-6790 (R140) Ro 63-0563	SB-258719 SB-269970 (S7389) Clozapine (C6305)
Signal Transduction Mechanism	Ligand-gated cation channel	Gs (increase cAMP)	Not Known	Gs (increase cAMP)	Gs (increase cAMP)
Radioligands of Choice	[3H]-(S)-Zacopride [3H]-BRL 43694	[3H]-GR 113808 [125I]-SB-207710	[3H]-5-CT [125I]-LSD	[3H]-5-CT [125I]-LSD	[3H]-5-CT
Tissue Expression	Striatum, hippocampus, substantia-nigra, autonomic nerve terminals, sensory neurons	Striatum, brainstem, substantia-nigra, cardiac muscle, parasympathetic nerve terminals, smooth muscle	Hippocampus, cortex, cerebellum, habenula, spinal cord	Caudate, putamen, nucleus accumbens, hippocampus, sup cervical ganglion	Hippocampus, hypothalamus, raphe nuclei, G-I and vascular smooth muscle, sympathetic ganglia
Physiological Function	Sympathetic and para-sympathetric neuro-excitation	Smooth muscle relaxation, cardiac contraction, cholinergic neuroexcitation	Not Known	Potentially modulation of central cholinergic neurones	Smooth muscle relaxation, CNS neuromodulation
Disease Relevance	Chemo- and radiation-induced emesis, IBS	IBS, potentially cognition, potentially heart failure	Not Known	Potential role in psychoses	Circadian phase shifts

Footnotes

a) Two genes encoding putative 5-ht₅ receptors have been identified in rodents and termed 5-ht_5A and 5-ht_5B. No human ortholog of the 5-ht_5B has been found.

b) The use of lower case denotes the identification of a gene product only.

c) Splice variants of the α-subunit exist in mouse.

d) Splice variants are denoted [a], [b] etc.

e) Putative rat rodent 5-ht_5B receptor: 371 370 aa.

Abbreviations

BIMU 8: (endo-N-8-Methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dihydro-3-isopropyl-2-oxo-1H-benzimidazol-1-carboxamide hydrochloride
5-CT: 5-Carboxamidotryptamine
GR 113808: [1-2[(Methylsuphonyl)amino]ethyl]-4-piperidinyl]methyl-1-methyl-1H-indole-3-carboxylate
5-HTQ: N,N,N-Trimethylserotonin iodide
LSD: Lysergic acid diethylamide
ML 10302: 2-(1-Piperidinyl)ethyl-4-amino-5-chloro-2-methoxybenzoate
Ro 04-6790: 4-Amino-N-(2,6 bis-methylamino-pyrimidin-4-yl)-benzene sulfonamide
Ro 63-0563: 4-Amino-N-(2,6 bis-methylamino-pyridin-4-yl)-benzene sulfonamide
RS 67506: 1-(4-Amino-5-chloro-2-methoxyphenyl)-3-(1-n-butyl-4-piperidinyl)-1-propanone
RS 100235: 1-(8-Amino-7-chloro-1,4-benzodioxan-5-yl)-5-((3-(3,4-dimethoxyphenyl)prop-1-yl)piperidin-4-yl)propan-1-one
SB-204070: 1-Butyl-4-piperidinylmethyl-8-amino-7-chloro-1,4-benzoioxan-5-carboxylate
SB-207710: 1-Butyl-4-piperidinylmethyl-8-amino-7-iodo-1,4-benzodioxan-5-carboxylate
SB-258719: (R)-3,N-Dimethyl-N-[1-methyl-3-(4-methylpiperidin-1-yl)propyl]benzenesulfonamide
SB-269970: (R)-1-[3-Hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine
SC 53116: (1S-cis)-4-Amino-5-chloro-N-[(hexahydro-1H-pyrrolizin-1-yl)methyl]-2-methoxybenzamide
SR 57227A: 4-Amino-(6-chloro-2-pyridyl)-1-piperidine hydrochloride.

h: human
r: rat

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