TABLE 1

Parameters characterizing the actions of the indicated allosteric agents and allosteric antagonists at porcine heart M2 receptors with the orthosteric site blocked by NMS

Agonist and Allosteric Agent Descriptors of Allosteric Agent Action Type of Antagonism Descriptors of Antagonist Action N
pEC0.5 dissn s log α log KB
Hexamethonium
   Duo3 6.08 ± 0.04 1.92 ± 0.26 Noncompetitivea 0.68 ± 0.06 3.59 ± 0.19b 16
   Tacrine 5.28 ± 0.01 1.74 ± 0.06 Cooperativec –0.92 ± 0.03 3.96 ± 0.06 17
   Tacrine dimer 6.56 ± 0.08 1.14 ± 0.15d Competitivee 0.78 ± 0.14d 3.48 ± 0.06 18
   WDuo3 8.30 ± 0.30 1.04 ± 0.59d Competitivee 0.73 ± 0.18d 4.32 ± 0.09 9
Mg2+
   Duo3 6.12 ± 0.02 1.32 ± 0.11 Competitivee 0.89 ± 0.20d 1.21 ± 0.07 9
   Tacrine 5.17 ± 0.02 1.93 ± 0.12 Cooperativec –0.77 ± 0.09 2.64 ± 0.04 10
   WDuo3 8.25 ± 0.02 0.97 ± 0.04d Competitivee 1.02 ± 0.13d 3.20 ± 0.06 9
Obidoxime
   Duo3 5.88 ± 0.02f 2.63 ± 0.41f Noncompetitivef 0.51 ± 0.04f 3.00 ± 0.08b 22
   Tacrine 5.17 ± 0.02 1.87 ± 0.12 Noncompetitivea 0.63 ± 0.02 3.89 ± 0.10b 11
   WDuo3 7.77 ± 0.04f 1.10 ± 0.09d,f Competitivef 0.94 ± 0.06d,f 4.16 ± 0.07f 16

  • pEC0.5diss, –log equilibrium dissociation constant of the allosteric agent: concentration causing a half-maximal reduction of the observed rate constant kobs of [3H]NMS dissociation in the absence of antagonist; n, slope factor of the corresponding curve. Type of antagonism, best fit model (see Materials and Methods); s, Schild slope; log α, log factor of cooperativity as a measure of the reciprocal effect on affinity between the respective antagonist and the respective allosteric agent (with log α < 0 indicating negative cooperativity); log KB, log equilibrium affinity constant of the allosteric antagonist; N, number of independent experiments.

  • ↵ a Eq. 1 with a linear Schild plot but a slope different from unity

  • ↵ b Value of pA2

  • ↵ c Eq. 2 [allosteric ternary complex model (Lazareno & Birdsall, 1995)]. Parameters n and s were constrained to 1, respectively, when they did not differ from unity (F test, p ≥ 0.05)

  • ↵ d Not significantly different from 1

  • ↵ e Eq. 1 [condensed Schild analysis (Lazareno & Birdsall, 1993)] with a Schild slope s not different from unity

  • ↵ f Data taken from Tränkle et al. (1997)