Target Validation Information
Target ID T50918
Target Name Muscarinic acetylcholine receptor M5
Target Type
Successful
Drug Potency against Target N-methoxyquinuclidine-3-carboximidoyl chloride Drug Info IC50 = 1100 nM
7-Pyrrolidin-1-yl-hept-5-yn-2-one Drug Info IC50 = 7280 nM
BRL-55473 Drug Info IC50 = 470 nM
Darifenacin Drug Info Ki = 10 nM [1]
3-Methyl-7-pyrrolidin-1-yl-hept-5-yn-2-one Drug Info IC50 = 5696 nM
4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one Drug Info Ki < 1000 nM [2]
N-DESMETHYLCLOZAPINE Drug Info Ki = 51 nM [2]
Pilocarpine Drug Info EC50 = 845 nM
N-(4-Dimethylamino-but-2-ynyl)-N-methyl-acetamide Drug Info IC50 = 21.6 nM
FM1-10 Drug Info Ki = 228 nM [3]
Acetic acid 8-aza-bicyclo[3.2.1]oct-6-yl ester Drug Info Ki = 0.95 nM [4]
Mepenzolate Drug Info IC50 = 1000 nM [5]
Pirenzepine Drug Info Ki = 63 nM [1]
ISOLOXAPINE Drug Info IC50 = 49 nM [6]
1'-Benzyl-3-phenyl-[3,4']bipiperidinyl-2,6-dione Drug Info IC50 = 15 nM [7]
Atropine Drug Info Ki = 0.63 nM [1]
3-Tetrazol-2-yl-1-aza-bicyclo[2.2.2]octane Drug Info IC50 = 16000 nM [8]
SULFOARECOLINE Drug Info IC50 = 1.4 nM [9]
7-Dimethylamino-hept-5-yn-2-one Drug Info IC50 = 68 nM
VU0238429 Drug Info Ki = 159 nM [10]
Tolterodine Drug Info Ki = 3.98 nM [1]
CREMASTRINE Drug Info IC50 = 1220 nM [11]
GNF-PF-5618 Drug Info Ki = 1180 nM [12]
1-Methyl-1-(4-pyrrolidin-1-yl-but-2-ynyl)-urea Drug Info Ki = 10700 nM [13]
2,8-Dimethyl-1-oxa-8-aza-spiro[4.5]decan-3-one Drug Info Ki = 6.7 nM [14]
Benzoic acid 8-aza-bicyclo[3.2.1]oct-6-yl ester Drug Info Ki = 440 nM [4]
Homatropine Methylbromide Drug Info IC50 = 9000000 nM
PF-3409409 Drug Info Ki = 1800 nM [15]
6-Dimethylamino-2-methyl-hex-4-ynal oxime Drug Info IC50 = 13230 nM
ISOCLOZAPINE Drug Info IC50 = 55 nM [16]
N-methoxyquinuclidine-3-carboximidoyl fluoride Drug Info IC50 = 2000 nM
FLUMEZAPINE Drug Info IC50 = 80 nM [17]
ACECLIDINE Drug Info IC50 = 510 nM [18]
FM1-43 Drug Info Ki = 83 nM [3]
7-Dimethylamino-3-methyl-hept-5-yn-2-one Drug Info IC50 = 101 nM
GSK961081 Drug Info Ki < 10 nM [19]
Procyclidine Drug Info IC50 =70 nM [20]
2-Methyl-6-pyrrolidin-1-yl-hex-4-ynal oxime Drug Info IC50 = 1928 nM
Action against Disease Model Trospium Trospi uM chloride is a quaternary ammoni uM compound, which is a competitive antagonist at muscarinic cholinergic receptors. Preclinical studies using porcine and h uMan detrusor muscle strips demonstrated that trospi uM chloride was many-fold more potent than oxybutynin and tolterodine in inhibiting contractile responses to carbachol and electrical stimulation. The drug ispoorly bioavailable orally (< 10%) and food reduces absorption by 70%- 80%. It is predominantly eliminated renally as unchanged compound. Trospi uM chloride, dosed 20 mg twice daily, is significantlysuperior to placebo in improving cystometric parameters, reducing urinary frequency, reducing incontinence episodes, and increasing urine vol uMe per micturition. In active-controlled trials, trospi uM chloride was at least equivalent to immediate-release formulations of oxybutynin and tolterodine in efficacy and tolerability. The most problematic adverse effects of trospi uM chloride are the anticholinergic effects of dry mouth and constipation. Comparative efficacy/tolerability data with long-acting formulations of oxybutynin and tolterodine as well as other anticholinergics such as solifenacin and darifenacin are not available. On the basis of available data, trospi uM chloride does not appear to be a substantial advance upon existing anticholinergics in the management of urge urinary incontinence. [21] Drug Info
Flavoxate flavoxate caused a concentration-dependent relaxation of h uMan urinary bladder precontracted by K+ with much higher potency (IC50: 2000 nM) Drug Info
Oxyphencyclimine Inhibition of H-Quinuclidinyl Benzilate (H-QNB) binding to Bovine Cortex. IC50 for (R)-(+)-Oxyphencyclimine HCL: 25.8 nM Drug Info
Promazine IC50 on SARS virus (Urbani strain) in African green monkey kidney cells: 11200nM [22] Drug Info
Ipratropium IC50 of EFS-induced contraction in Guinea pig/h uMan trachea: 0.58 nM/1.36 nM [23] Drug Info
Bethanechol IC50 for porcine and h uMan detrusor muscle: 80000 nM [24] Drug Info
References
REF 1Therapeutic opportunities from muscarinic receptor research. Trends Pharmacol Sci. 2001 Aug;22(8):409-14.
REF 2J Med Chem. 2010 Sep 9;53(17):6386-97.Discovery of N-{1-[3-(3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)propyl]piperidin-4-yl}-2-phenylacetamide (Lu AE51090): an allosteric muscarinic M1 receptor agonist with unprecedented selectivity and procognitive potential.
REF 3Bioorg Med Chem Lett. 2008 Jan 15;18(2):825-7. Epub 2007 Nov 17.Design and synthesis of a fluorescent muscarinic antagonist.
REF 4J Med Chem. 2000 Jun 29;43(13):2514-22.6beta-Acyloxy(nor)tropanes: affinities for antagonist/agonist binding sites on transfected and native muscarinic receptors.
REF 5Low temperature and muscarinic receptor activities. Cryobiology. 1989 Oct;26(5):485-95.
REF 6J Med Chem. 1981 Sep;24(9):1021-6.Synthesis of clozapine analogues and their affinity for clozapine and spiroperidol binding sites in rat brain.
REF 7J Med Chem. 1989 May;32(5):1057-62.Synthesis and biological evaluation of [125I]- and [123I]-4-iododexetimide, a potent muscarinic cholinergic receptor antagonist.
REF 8J Med Chem. 1992 Apr 3;35(7):1280-90.Synthesis and muscarinic activities of quinuclidin-3-yltriazole and -tetrazole derivatives.
REF 9J Med Chem. 1988 Jul;31(7):1312-6.Heterocyclic muscarinic agonists. Synthesis and biological activity of some bicyclic sulfonium arecoline bioisosteres.
REF 10J Med Chem. 2009 Jun 11;52(11):3445-8.Discovery of the first highly M5-preferring muscarinic acetylcholine receptor ligand, an M5 positive allosteric modulator derived from a series of 5-trifluoromethoxy N-benzyl isatins.
REF 11J Nat Prod. 2005 Apr;68(4):572-3.Cremastrine, a pyrrolizidine alkaloid from Cremastra appendiculata.
REF 12J Nat Prod. 2005 Jul;68(7):1061-5.Nocardimicins A, B, C, D, E, and F, siderophores with muscarinic M3 receptor inhibiting activity from Nocardia sp. TP-A0674.
REF 13J Med Chem. 1992 Aug 21;35(17):3270-9.Urea and 2-imidazolidone derivatives of the muscarinic agents oxotremorine and N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide.
REF 14J Med Chem. 1998 Oct 22;41(22):4181-5.Synthesis and modeling studies of a potent conformationally rigid muscarinic agonist: 1-azabicyclo[2.2.1]heptanespirofuranone.
REF 15Bioorg Med Chem Lett. 2009 Aug 15;19(16):4579-83. Epub 2009 Jul 2.Design, synthesis and evaluation of N-[(3S)-pyrrolidin-3-yl]benzamides as selective noradrenaline reuptake inhibitors: CNS penetration in a more polar template.
REF 16J Med Chem. 1990 Feb;33(2):809-14.Chloro-substituted, sterically hindered 5,11-dicarbo analogues of clozapine as potential chiral antipsychotic agents.
REF 17J Med Chem. 1989 Dec;32(12):2573-82.Synthesis and pharmacological evaluation of a series of 4-piperazinylpyrazolo[3,4-b]- and -[4,3-b][1,5]benzodiazepines as potential anxiolytics.
REF 18J Med Chem. 1993 Apr 2;36(7):842-7.Design, synthesis, and neurochemical evaluation of 5-(3-alkyl-1,2,4- oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidines as M1 muscarinic receptor agonists.
REF 19Muscarinic antagonist-beta-adrenergic agonist dual pharmacology molecules as bronchodilators: a patent review. Expert Opin Ther Pat. 2009 Jan;19(1):1-12. doi: 10.1517/13543770802630331.
REF 20Effects of antiparkinsonian drugs on muscarinic receptor binding in rat brain, heart and lung. Pharmacol Toxicol. 1988 Feb;62(2):90-4.
REF 21Trospium chloride: an update on a quaternary anticholinergic for treatment of urge urinary incontinence. Ther Clin Risk Manag. 2005 Jun;1(2):157-67.
REF 22Is the anti-psychotic, 10-(3-(dimethylamino)propyl)phenothiazine (promazine), a potential drug with which to treat SARS infections? Lack of efficacy of promazine on SARS-CoV replication in a mouse model. Antiviral Res. 2008 Aug;79(2):105-13. doi: 10.1016/j.antiviral.2007.12.005. Epub 2008 Jan 11.
REF 23Pharmacological characterization of the muscarinic receptor antagonist, glycopyrrolate, in human and guinea-pig airways. Br J Pharmacol. 1999 May;127(2):413-20.
REF 24[3H]QNB binding and contraction of rabbit colonic smooth muscle cells. Am J Physiol. 1987 Nov;253(5 Pt 1):G656-61.

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