TABLE 1

IC₅₀ values for inhibition of MPP transport into CHO cells stably expressed with either hMATE1 or hMATE2-K

Each value determined at pH 8.5 is a mean IC₅₀ (in μM; ± S.E.M.) of two to four experiments. IC₅₀ values listed for pH 7.4 were calculated. Underlined compounds indicate the compounds that comprised the initial set of 24 organic molecules used is in the first iteration of pharamacophore development; superscript a indicates the 15 compounds used to test the common features pharmacophore; and italicized compounds are those identified by the pharmacophores from the list of FDA-approved drugs during the course of model development.

Compound	Drug Class	MATE1 IC₅₀ pH 8.5	MATE1 Calculated IC₅₀ pH 7.4	MATE2-K IC₅₀ pH 8.5	MATE2-K Calculated IC₅₀ pH 7.4
		μM		μM
Agmatine	NT	53.9 ± 1.4	140	60.8 ± 9.1	400
Allopurinol	XAI	NI	N.A.	NI	N.A.
Amantadine	AV	7.53 ± 1.49	20	88.9 ± 9.0	580
Amiloride	DI	2.41 ± 0.18	6.3	3.06 ± 0.62	20
APMI	PAL	6.21 ± 0.26	16	0.501 ± 0.224	3.3
Atropine	AC	5.9 ± 1.3	15	52.8 ± 13.7	340
Baclofen	AS, MR	NI	N.A.	NI	N.A.
Caffeine	S	1096 ± 43	2900	451 ± 120	2900
Chloramphenicol	AB	1114 ± 156	2900	1951 ± 45	13,000
Cinchonidine^a	SC	0.927 ± 0.154	2.4	4.38 ± 1.16	27
Cinchonine^a	SC	1.86 ± 0.38	4.8	0.939 ± 0.043	5.8
Cisplatin	CT	NI	N.A.	NI	N.A.
Clonidine	A2A	8.09 ± 0.79	21	54.0 ± 1.3	350
Creatinine	MBP	195 ± 39	510	150 ± 26	980
Ethohexadiol^a	IR	>2000	N.A.	>1000	N.A.
Famotidine^a	H2RA	2.16 ± 0.39	5.6	6.28 ± 0.45	39
Guanfacine	A2AN	3.5 ± 1.2	9.2	218 ± 64	1300
Guanidine	MBP	>2100	5400	>4000	N.A.
H⁺	EI	0.020 ± 0.001	N.A.	0.004 ± 0.001	N.A.
Histamine	IRR, NT	761 ± 196	2000	775 ± 148	5000
Imiquimod^a	IMR	13.9 ± 5.9	36	19.1 ± 5.7	120
Ketoconazole	AF	1.33 ± 0.17	3.4	9.33 ± 0.81	58
Metformin	AD	47.0 ± 2.2	120	89.3 ± 17.7	580
Midodrine^a	VP	109 ± 18	280	87.1 ± 38.4	540
MPP	NTX	4.70 ± 0.55	12	3.3 ± 0.2	21
Naloxone^a	OAN	24.1 ± 3.7	62	43.2 ± 12.9	280
Nialamide^a	MAOI	212 ± 5	550	236 ± 31	1500
Nicotine	S	167 ± 37	440	134 ± 28	870
Nicotinamide mononucleotide	POC	147 ± 81	390	46.3 ± 5.3	500
Paraquat	H	50.5 ± 7.7	130	15.5 ± 1.3	100
Phenformin	AD	6.10 ± 0.19	16	11.2 ± 2.8	73
Phentolamine^a	AAA	4.64 ± 0.37	12	5.3 ± 0.5	33
Procainamide	AA	24.0 ± 1.3	63	19.1 ± 3.4	120
Proguanil^a	AM	4.35 ± 1.70	11	1.39 ± 0.51	9.0
Propranolol^a	BB	7.81 ± 038	20	7.71 ± 0.10	48
PYR	AM	0.04 ± 0.01	0.11	0.059 ± 0.015	0.38
PYR-2	SC	0.14 ± 0.01	0.35	0.068 ± 0.026	0.44
PYR-3	SC	0.20 ± 0.01	0.51	0.058 ± 0.009	0.38
Quinidine	AA	1.57 ± 0.32	4.1	1.47 ± 0.27	9.6
Quinine^a	AA	1.90 ± 0.41	5.0	6.4 ± 1.7	42
Ranitidine	H2RA	5.40 ± 1.02	14	10.0 ± 1.9	65
Scopolamine^a	AC, AMS	47.6 ± 4.8	120	272 ± 25	1700
Serotonin	MA, NT	28.8 ± 5.3	75	18.3 ± 1.4	120
Sulfadimethoxine	AB	>>1000	N.A.	>>1000	N.A.
Sulfamerazine	AB	>>1000	N.A.	>>1000	N.A.
Tacrine	ACS	0.51 ± 0.10	1.3	1.10 ± 0.21	7.2
Tetrabutylammonium	SC	11.6 ± 1.8	30	N.A.	N.A.
TEA	POC	40.6 ± 4.6	110	14.4 ± 8.8	94
Triethylmethylammonium	SC	51.6 ± 10.2	140	28.4 ± 0.7	180
Ticlopidine	AP	>1000	N.A.	>1000	N.A.
Tetramethylammonium	SC	>5000	N.A.	N.A.	N.A.
Topiramate^a	ACT	∼1000	N.A.	NI	N.A.
TPeA	SC	6.34 ± 0.23	16	N.A.	N.A.
Tetrapropylammonium	SC	14.8 ± 4.0	39	N.A.	N.A.
Tramadol	OA	17.8 ± 1.6	46	74.6 ± 17.6	490
Trichlormethiazide^a	DI	249 ± 10	640	679 ± 10	4200
Trimethoprim	AB	9.70 ± 1.2	225	2.61 ± 1.12	17
Tryptophan	AAM	NI	N.A.	NI	N.A.
Tyramine	MA	86.6 ± 8.2	230	138 ± 11	900
Verapamil	LTCB	41.9 ± 6.8	110	37.9 ± 9.7	250

N.A., not available; A2A, α-2 adrenergic agonist; A2AN, α-2A norepinephrin receptor agonist; AA, antiarrhythmic; AAA, α adrenergic antagonist; AAC, amino acid; AB, antibiotic; AC, anticholinergic; ACS, anticholinesterase; ACT, anticonvulsant; AD, antidiabetic; AF, antifungal; AM, antimalarial; AMS, antimuscurinic; AP, antiplatelet; AS, antispastic; AV, antiviral; BB, β blocker; CT, chemotherapy drug; DI, diuretic; EI, endogenous ion; H, herbicide; H2RA, histamine H2-receptor antagonist; IMR, immune response modifier; IR, insect repellent; IRR, immune response regulator; LTCB, L-type calcium blocker; MA, monoamine; MAOI, monoamine oxidase inhibitor; MBP, metabolism by-product; MS, muscle relaxant; NT, neurotransmitter; NTX, neurotoxin; OA, opiate agonist; OAN, opiate antagonist; PAL, photoaffinity label; POC, prototypical organic cation; S, stimulant; SC, synthetic chemical; VP, vasopressor; XOI, xanthine oxidase inhibitor; NI, no interaction.