Table I.

Structures of Telenzepine Derivatives Synthesized and Their Affinity at Muscarinic Receptors

no.	R	receptor subtype and Ki valuesa (nM)
		forebrain	heart	other
1	—CH3 (telenzepine)	4.67 ± 0.53	66.9 ± 32	m1 (A9L), 1.8; m3, 6.9; m4,17.4
2	—H	b	b
4	—(CH2)10NH2	b	3.7	m1 (A9L), 2.39; m3, 7.5; m4, 1.3
5		2.22 ± 0.48	1.75 ± 0.52
6		0.29 ± 0.03	0.31 ± 0.07
7		b	b
8		1.25 ± 0.12	3.7 ± 0.5
9		3.20 ± 1.33	0.60 ± 0.22
10		42.5 ± 10.0	43.7 ± 12.2
11		10.5 ± 0.7	b
12		116 ± 17.5	82.1 ± 11
13		1.21 ± 0.12	1.38 ± 0.15
14		20.1 ± 6.2	b
15		11.8 ± 3.4	b

^aK_i values for inhibition of binding of [³H]NMS are given. Values are expressed as average for a single experiment run in triplicate or as mean ± SEM for three experiments. Membranes from rat brain (mostly m₁-receptors) or rat heart (m₂-receptors) were isolated as described in Experimental Procedures. Varying concentrations of compound were incubated with 0.5 nM [³H]NMS and a quantity of membranes containing 100–300 μg of protein for 60 min at 37 °C and then rapidly filtered over GF/B filters. Competition binding experiments using membranes from transfected A9L cells (m₁- and m₃-receptors) and from NG108–15 cells (m₄-receptors) were carried out as previously described (14). The resulting data were analyzed by nonlinear regression, and IC₅₀ values were converted to K_i values using the Cheng–Prusoff equation (15) with the following K_d values for [³H]NMS binding: 0.350 nM with brain membranes and 0.425 nM with cardiac membranes.

^bNot determined.