Neurotransmitters and other chemical signalling agents

Small-molecule neurotransmitters
- Acetylcholine
- Adenosine
- ATP
- Monoamines (biogenic amines)
- Excitatory amino acids
  - Glutamate and aspartate
- Inhibitory amino acids
  - GABA
  - Glycine
Neuropeptides and other substances

Small-molecule neurotransmitters

Acetylcholine (ACh)

Precursors:	Choline and acetyl-CoA
Synthesising enzymes:	Choline acetyl transferase
Metabolising enzymes:	Acetylcholinesterase
Metabolite:	Choline and acetate

Receptor subtypes	Agonists	Antagonists	Second messenger
M1 muscarinic	Methacholine	Pirenzepine, telenzepine	PI
M2	Methacholine	Himbacine, methoctramine	(-ve)cAMP, (+ve)gK+
M3	Methacholine	Hexahydrosila- difenidol	PI
M4 M5 MB	Methacholine	Tropicamide	(-ve)cAMP PI
Nicotinic (neuronal/ ganglion type)	Dimethylphenyl- piperazinium, nicotine	mecamylamine, hexamethonium ((+)tubocurarine blocks channel)	(+ve)g(cation)
Nicotinic (muscle type)	Suxamethonium (also causes depolarisation block)	alpha-bungarotoxin, (+)tubocurarine (decamethonium blocks channel)	(+ve)g(cation)

Adenosine (P₁ purinoceptors)

Precursors:		Mainly AMP (from released ATP)
Synthesising enzymes:		Mainly 5'-nucleotidase
Metabolising enzymes:		Adenosine deaminase
Metabolite:		Inosine

Receptor subtypes	Agonists	Antagonists	Second messenger
A₁	CPA, R-PIA, GR 79236	8PT, DPCPX	(-ve)cAMP
A₂A	CGS21680, CV-1808	8PT, CGS 15943	(+ve)cAMP
A₂B	Metrifudil	8PT	(+ve)cAMP
A₃ MB	R-PIA, NECA	none	(-ve)cAMP

ATP (P₂ purinoceptors)

Precursors:		Normal cellular constituent; formed from ADP
Synthesising enzymes:		Phosphorylases
Metabolising enzymes:		Phosphatases
Metabolites:		ADP, AMP, adenosine, inosine

Receptor subtypes	Agonists	Antagonists	Second messenger
P_2X	beta-gamma-Me-ATP	alpha-beta-Me-ATP (desensitises) suramin	(+ve)g(cation) or (up)gCa²⁺
P_2Y	ADP-beta-F, 2-Me-S-ATP	Reactive blue 2, suramin	PI, (+ve)gK
P_2T (platelet)	ADP	Suramin, AMP	(-ve) cAMP, (+ve)g(cation)
P_2Z (mast cell)	ATP^4-	none	?
P_2U	UTP	none	PI

Monoamines (biogenic amines)

Norepinephrine (Noradrenaline; NA) and Epinephrine (Adrenaline; AD)

Precursors:	L-Tyrosine (a) -> L-DOPA (b) -> dopamine (c) -> noradrenaline (d) -> adrenaline
Synthesising enzymes:	(a) tyrosine hydroxylase, (b) L-aromatic amino-acid decarboxylase, (c) dopamine-beta-hydroxylase, (d) phenylethanolamine-N-methyl transferase
Metabolising enzymes:	MAO and COMT
Metabolites:	Vanillylmandelic acid (VMA) and 3-methoxy-4-hydroxyphenylglycol (MHPG)

Receptor subtypes	Agonists	Antagonists	Second messenger
alpha_(1A)	Phenylephrine	Prazosin, (+)-niguldipine	PI
alpha_(1B)	Phenylephrine	Prazosin, CEC	PI
alpha_(1C)	Phenylephrine	Prazosin, CEC	PI
alpha_(2A)	Oxymetazoline	Yohimbine, fluparoxan	(-ve)cAMP, (down)gCa⁽²⁺⁾, (down)gK+
alpha_(2B)	UK14304	Prazosin, ARC 239	(-ve)cAMP, (down)gCa⁽²⁺⁾
alpha_(2C)	UK14304	Yohimbine	(-ve)cAMP
beta₍₁₎	Xamoterol, RD363	Practolol, atenolol, CGP20712A	(+ve)cAMP
beta₍₂₎	Salbutamol, salmeterol, procaterol	ICI 118551	(+ve)cAMP
beta₍₃₎	BRL 37344 BRL 35135	cyanopindolol	(+ve)cAMP

Dopamine (DA)

Precursors:	Tyrosine (a) -> L-dihydroxyphenylalanine (L-DOPA) (b) -7gt; dopamine
Synthesising enzymes:	(a) Tyrosine hydroxylase; (b) L-aromatic amino-acid decarboxylase (DOPA decarboxylase)
Metabolising enzymes:	MAO and catechol-O-methyl transferase (COMT)
Metabolite:	3,4-Dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA)

Receptor subtypes	Agonists	Antagonists	Second messenger
D₁	SKF 38393	Sch 23390	(+ve) cAMP
D₂	Quinpirole	Sulpiride	(+ve)gK+
D₃	7-OH-DPAT	AJ-76	?
D₄	Dopamine	Clozapine	?
D₅	Dopamine	Sch 23390	(+ve)cAMP

5-Hydroxytryptamine (5-HT; serotonin)

Precursors:		Tryptophan (a) -> 5-hydroxytryptophan (b) -> 5HT
Synthesising enzymes:		(a) Tryptophan hydroxylase, (b) 5HTP decarboxylase
Metabolising enzymes:		Monoamine oxidase (MAO)
Metabolite:		5HIAA

Receptor subtypes	Agonists	Antagonists	Second messenger
5HT_(1A)	8-OH-DPAT	Way 100135, SDZ 216-525	(-ve) cAMP
5HT_(1B)	CP 93129	Cyanopindolol	(-ve) cAMP
5HT_(1C)	now re-classified as 5HT_(2C)
5HT_(1D)	5CT, sumatriptan	Methiothepin, methysergide	(-ve) cAMP
5HT_(1D-alpha) MB
5HT_(1DB) MB (human homologue of the rodent 5HT1B receptor)
5HT_(1E-alpha) MB			(-ve) cAMP
5HT_(1EB) MB			(-ve) cAMP
5HT_(1F) MB			(-ve) cAMP
5HT_(2A) (old 5HT₍₂₎)	DOI	Ketanserin	PI
5HT_(2B) (rat fundus)	DOI	Ketanserin	PI
5HT_(2C) (old 5HT1C)	mCPP	Mesulergine	PI
5HT₍₃₎	2-Me-5HT	Ondansetron, granisetron	(+ve)g(cation)
5HT₍₄₎	5MeOTrp, cisapride	GR 113808	(+ve)cAMP
5HT₍₅₎ MB	(binds bufotenine)

Histamine (HA)

Precursors:	Histidine
Synthesising enzymes:	Histidine decarboxylase
Metabolising enzymes:	Histamine-N-methyl transferase, histaminase, etc.
Metabolite:	Methylhistamine, IAA and others

Receptor subtypes	Agonists	Antagonists	Second messenger
H₍₁₎	2-thiazolyl- ethylamine	Mepyramine	PI
H₍₂₎	Dimaprit	Ranitidine, cimetidine	(+ve)cAMP
H₍₃₎	(R)-alpha-methyl histamine	Thioperamide	?

Excitatory amino acids (EAA)

Glutamate (Glu) (and Aspartate)

Precursors:		None
Synthesising enzymes:		None
Metabolising enzymes:		Glutamate transaminase (uptake is more important)
Metabolite:		Glutamine

Receptor subtypes	Agonists	Antagonists	Second messenger
NMDA (subtypes MB)	NMDA, AP5, CPP	CGP37849 (MK801 is a channel blocker, PCP is non-competitive)	(+ve)g(cation)
AMPA (subtypes MB)	AMPA, quisqualate	NBQX, NQX DNQX	(+ve)g(cation)
Kainate (subtypes MB)	Kainate, domoate	NBQX, NQX DNQX	(+ve)g(cation)
Metabotropic (subtypes MB)	1S,3R-ACPD, ibotenate	None	PI

Inhibitory amino acids (IAA)

gamma-Aminobutyric Acid (GABA)

Precursors:		Glutamate
Synthesising enzymes:		Glutamic acid decarboxylase (GAD)
Metabolising enzymes:		GABA transaminase
Metabolite:		Succinic semialdehyde

Receptor subtypes	Agonists	Antagonists	Second messenger
GABA_A	Muscimol, THIP, isoguvacin	Bicuculline, picrotoxin	(+ve)gCl
GABA_B	Baclofen, CGP 97541	2-OH-Saclofen, CGP 35348	(-ve)gK+, (-ve)gCa2+, (-ve)cAMP
Benzodiazepine site on GABAA receptor	Diazepam (DMCM is an inverse agonist)	Flumazenil	Enhances (+ve)gCl- by GABA

Glycine (Gly)

Precursors:		None
Synthesising enzymes:		None
etabolising enzymes:		None (uptake is more important)
Metabolite:		None

Receptor subtypes	Agonists	Antagonists	Second messenger
Glycine	Glycine	Strychnine	(+ve)gCl-
Allosteric site on NMDA receptor	Glycine	7-chloro-kynurenate	n/a

Large-molecule neurotransmitters (neuropeptides) and other substances

Angiotensin II (AT II)

Precursors:		Angiotensin I
Synthesising enzymes:		Angiotensin converting enzyme (ACE)
Metabolising enzymes:		Aminopeptidase
Metabolite:		Angiotensin III

Receptor subtypes	Agonists	Antagonists	Second messenger
AT₁	Angiotensin II,III	Losartan (DuP753), GR 117289	PI, (-ve)cAMP
AT₂	Angiotensin II,III	PD 123177, PD 123319, CGP42112	(-ve)cGMP

Bradykinin (BK)

Precursors:		Kininogens
Synthesising enzyme:		Kallikrein
Metabolising enzyme:		ACE, kininase I (carboxypeptidase-N)
Metabolites:		Des-Arg9-bradykinin, other fragments

Receptor subtypes	Agonists	Antagonists	Second messenger
B₁	Des-Arg⁹-BK	Des-Arg⁹, Leu⁸-BK Des-Arg¹⁰-HOE140	?
B₂	Hyp⁹,Tyr(Me)⁸-BK	NPC567, HOE140, NPC349	PI

Cholecystokinin (CCK) (and Gastrin (G))

Precursors:		Preprocholecystokinin
Synthesising enzymes:		Post-translational peptidases
Metabolising enzymes:		Endopeptidase EC 24:11
Metabolite:		Peptide fragments

Receptor subtypes	Agonists	Antagonists	Second messenger
CCK_(A)	A71378	Devazepide, lorglumide	PI
CCK_(B)	CCK4	L365260, PD134308	?
Gastrin *	G17	L365260	PI

* may be identical to CCK_(B)

Enkephalin (met- and leu-) and Dynorphin

Precursors:		Proenkephalin and prodynorphin
Synthesising enzymes:		Peptidases
Metabolising enzymes:		Enkephalinase (EC 24:11) and other peptidases
Metabolite:		Peptide fragments

Receptor subtypes	Agonists	Antagonists	Second messenger
µ-opoid	DAGOL (DAMGO)	Naloxone	(-ve)cAMP, (+ve)gK+
delta-opoid	DPDPE	Naltrindol	(-ve)cAMP, (+ve)gK+
kappa-opoid	U69593, CI 977, dynorphin	Norbinaltorphimine	(-ve)gCa²⁺

Endothelin (ET)

Precursors:		preproET-1 etc.
Synthesising enzymes:		"endothelin converting enzyme"
Metabolising enzymes:		not known

Receptor subtypes	Agonists	Antagonists	Second messenger
ET_(A)	ET-1, ET-2	FR139317, BQ123	PI
ET_(B)	Sarafotoxin S6C, [Ala^{(1),(3),(11),(15)}] ET-1, BQ 3020	IRL 1038	PI
ET_(C) MB

Nitric Oxide (NO; formerly EDRF)

Precursors:		L-arginine
Synthesising enzymes:		NO synthase
Metabolising enzymes:		none: diffusion and spontaneous breakdown
Metabolite:		NO₍₂₎^-, NO₍₃₎^-

NO has no conventional receptor, but it activates guanylate cyclase directly. It can be generated by glyceryl trinitrate or sodium nitroprusside. The synthetic enzyme can be inhibited by L-NMMA and L-NAME. Three NO synthases have been cloned, of which one (in macrophages) is\inducible, and two (in brain and endothelium) are constitutive.

Prostanoids (Prostaglandins, prostacyclin and thromboxane)

Precursors:		rachidonic acid (i.e. eicosatetraenoic acid; 2-series prostanoids), eicosatri- and eicosapentaenoic acids
Synthesising enzymes:		Prostaglandin synthetase (cyclooxygenase), PGI2 synthase, TX synthase.
Metabolising enzymes:		15-hydroxyprostaglandin dehydrogenase, PG-9-keto-reductase
Metabolites:		large number of oxidised metabolites

Receptor subtypes (most potent natural prostanoid)	Agonists	Antagonists	Second messenger
DP (PGD₍₂₎)	BW245C, ZK110841	BWA868C, AH6809	<87>cAMP
EP (PGE₍₂₎), subdivided as shown:
EP₍₁₎	sulprostone, iloprost	AH6809, SC-19220	PI
EP₍₂₎	AY23626, butaprost, rioprostil	none	<87>cAMP
EP₍₃₎	sulprostone AY23626, rioprostil, enprostil, GR 63799	none	PI, <51>cAMP
FP (PGF_(2-alpha))	fluprostenol, cloprostenol	none	PI
IP (PGI₍₂₎)	iloprost,cicaprost	none	<87>cAMP
TP (TXA₍₂₎)	U-46619, STA2, EP171	GR32191, EP092, BM13505, SQ28668	PI

Substance P (SP) and Neurokinins A and B (NKA, NKB)

Precursors:		Preprotachykinins
Synthesising enzymes:		Peptidases
Metabolising enzymes:		ACh-esterase, EC 24.11
Metabolite:		Peptide fragments

Receptor subtypes	Agonists	Antagonists	Second messenger
NK₍₁₎	SPOMe, GR 73632, Sar⁹Met(O₂)¹¹SP	GR82334, RP67580, CP-99994	PI
NK₍₂₎	GR 64349	L-659877, SR48968, MEN10207, GR94800 GR100679	PI
NK₍₃₎	Senktide	GR138676	PI

Other neurotransmitter substances

Neurotransmitter	Abbreviation
Antidiuretic hormone (vasopressin)	ADH
Atrial natriuretic peptide	ANP or ANF
Bombesin
Calcitonin-gene-related peptide	CGRP
Corticotrophin-releasing factor	CRF
Galanin	--
Leukotriene	LT
Luteinising hormone releasing hormone	LHRH
Melatonin	--
Neuropeptide Y	NPY
Neurotensin	NT
Oxytocin	--
Pancreatic polypeptide (human)	(h)PP
Peptide YY	PYY
Platelet aggregating factor	PAF
Somatostatin	SS or SRIF
Taurine	--
Thyrotropin-releasing hormone	TRH
Vasoactive intestinal polypeptide	VIP

NB: (+ve) indicates increase; (-ve) indicates decrease.