Table 3. Antagonist Properties and Binding Data of Compounds 12–28, Ondansetron, and Intepirdine at 5-HT₃ and 5-HT₆ Receptors Suggest That Dual-Acting 5-HT₃/5-HT₆R Antagonists (17, 18, 20) Display the Most Favorable Profile.

			5-HT3R		5-HT6R
compound	Ar	R	antagonist effecta	pD2′b	antagonist effectc	Kb [nM]d	Ki [nM]e
12	3-F-Ph	CH3	30 (30 nM) 74 (100 nM)	7.33	83	6	2
13	3-Cl-Ph	CH3	10 (100 nM) 44 (300 nM)	NT	90	5	2
14	4-F-Ph	CH3	NT	NT	75	7	10
15	2-Br-Ph	H	NT	NT	69	NT	13
16	2-Cl-Ph	H	NT	NT	75	50	5
17 FPPQ	3-F-Ph	H	32 (100 nM) 78 (300 nM)	7.43	92	2	3
18	3-Cl-Ph	H	11 (100 nM) 72	6.71	100	32	3
19	3-CF3-Ph	H	21 (100 nM) 37 (300 nM)	6.09	82	17	3
20	3-Me-Ph	H	20 (30 nM) 40 (100 nM)	6.74	89	38	3
21	3-OMe-Ph	H	28 (100 nM) 73 (300 nM)	6.38	82	32	7
22	4-F-Ph	H	48 (300 nM)	NT	72	NT	18
23	4-CF3-Ph	H	NT	NT	63	NT	34
24	4-iPr-Ph	H	38 (300 nM)	NT	65	NT	14
25	3,4-diF-Ph	H	NT	NT	56	124	18
26	3,4-diCl-Ph	H	NT	NT	70	58	12
27	2,5-diF-Ph	H	32 (300 nM)	NT	88	9	4
28	1-naphthyl	H	NT	NT	95	18	14
ondansetron			NT	pA2 = 7.11	1	58 220	NT
intepirdine			NT	NT	NT	1.2	1.4

^aPercent inhibition of response to stimulation by 5-HT (contraction of guinea pig ileum) at the concentration of 3 μM induced by different concentrations of test compounds shown in brackets (N = 6–8, SEM ≤ 12%).

^bAntagonist potency expressed as pD₂′ or pA₂(N = 6–8, SEM ≤ 0.19).

^cPercent inhibition of control agonist (5-HT) response at 10^–6 M; performed in duplicate in 1321N1 cells.

^dMean K_b values based on two independent experiments in 1321N1 cells (SEM ≤ 22%).

^eMean K_i values based on three independent binding experiments (SEM ≤ 15%).