(neuro)

Neurotransmitters and other chemical signalling agents

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

P2X

beta-gamma-Me-ATP

alpha-beta-Me-ATP
(desensitises)
suramin

(+ve)g(cation) or
(up)gCa2+

P2Y

ADP-beta-F,
2-Me-S-ATP

Reactive blue 2,
suramin

PI, (+ve)gK

P2T (platelet)

ADP

Suramin, AMP

(-ve) cAMP,
(+ve)g(cation)

P2Z
(mast cell)

ATP4-

none

?

P2U

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

GABAA

Muscimol, THIP,
isoguvacin

Bicuculline,
picrotoxin

(+ve)gCl

GABAB

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

Metabolising 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.

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