Percentage inhibition of [3H]NMS dissociation from muscarinic receptors by indolocarbazoles
| Name | M1 | M2 | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| pK | Slope | Emax | estd pK | diff | pK | Slope | Emax | estd pK | diff | ||
| Staurosporine | Mean | 6.01 | 1.00 | 104.7 | 6.10 | −0.09 | 5.40 | 1.00 | 90.8 | 5.31 | 0.09 |
| SEM | 0.08 | 0.00 | 5.3 | 0.04 | 0.02 | 0.00 | 8.3 | 0.06 | |||
| Go 7874 | Mean | 5.70* | 1.34 | 100.0 | 5.50* | 0.19 | 5.30* | 1.31 | 100.0 | 4.85* | 0.45 |
| SEM | 0.02 | 0.01 | 0.0 | 0.19 | 0.01 | 0.01 | 0.0 | 0.16 | |||
| KT 5823 | Mean | 6.40* | 1.00 | 103.6 | 6.58 | −0.18 | 6.21* | 1.00 | 77.9 | 6.18* | 0.02 |
| SEM | 0.01 | 0.00 | 3.2 | 0.08 | 0.05 | 0.00 | 2.0 | 0.18 | |||
| KT 5720 | Mean | 6.18 | 1.00 | 56.8 | 6.70 | −0.52 | |||||
| SEM | 0.15 | 0.00 | 3.8 | 0.09 | |||||||
| K-252a | Mean | 5.54* | 1.40 | 100.0 | 5.65* | 1.00 | 35.1 | ||||
| SEM | 0.01 | 0.07 | 0.0 | 0.00 | 0.00 | 2.4 | |||||
| Name | M3 | M4 | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| pK | Slope | Emax | estd pK | diff | pK | Slope | Emax | estd pK | diff | ||
| Staurosporine | Mean | 5.48 | 1.00 | 67.1 | 5.61 | 1.00 | 88.0 | 5.25 | 0.36 | ||
| SEM | 0.07 | 0.00 | 2.7 | 0.08 | 0.00 | 6.2 | 0.08 | ||||
| Go 7874 | Mean | 5.05* | 1.00 | 39.5 | 4.60* | 0.45 | 5.71* | 1.64 | 100.0 | 5.60* | 0.11 |
| SEM | 0.28 | 0.00 | 14.0 | 0.15 | 0.03 | 0.35 | 0.0 | 0.10 | |||
| KT 5823 | Mean | 6.45* | 1.00 | 29.8 | 5.88* | 1.00 | 41.5 | ||||
| SEM | 0.08 | 0.00 | 5.7 | 0.04 | 0.00 | 4.4 | |||||
| KT 5720 | Mean | 6.66 | 1.00 | 38.7 | 6.33 | 1.00 | 24.7 | 6.38* | −0.05 | ||
| SEM | 0.15 | 0.00 | 1.5 | 0.08 | 0.00 | 0.2 | 0.24 | ||||
| K-252a | Mean | 5.55* | 1.00 | 37.1 | 5.37* | 1.00 | 49.0 | ||||
| SEM | 0.00 | 0.00 | 4.2 | 0.02 | 0.00 | 5.8 | |||||
Curves such as those shown in Fig. 4 were fitted to a logistic equation as described in Experimental Procedures.
The estd pK is the product of affinity for the free receptor and cooperativity with [3H]NMS derived from the equilibrium binding assays summarized in Table 1. diff is the difference between the observed pK (-log IC50) and estd pK. The results are from at least three assays, except for *n = 2. Empty cells indicate that it was not possible to obtain at least two sets of parameter estimates. The [3H]NMS dissociation rate constants (min−1) observed in this study are (mean ± SEM (n)) M1 0.058 ± 0.002 (26); M2 0.34 ± 0.01 (12); M3 0.054 ± 0.002 (10); M4 0.057 ± 0.002 (10).