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Characteristics of cyanopindolol analogues active at the β 3 ‐adrenoceptor in rat ileum
Author(s) -
Hoey Andrew J.,
Jackson Clifford M.,
Pegg Graham G.,
Sillence Martin N.
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15709.x
Subject(s) - pindolol , antagonist , chemistry , stereochemistry , agonist , competitive antagonist , pharmacology , receptor , biology , biochemistry
1 Cyanopindolol (CYP) is a potent antagonist at the β 3 ‐adrenoceptor in rat ileum. Several analogues of CYP and pindolol were synthesized that also produced antagonist effects at the β 3 ‐adrenoceptor. However, at high concentrations, these compounds appear to act as ‘partial agonists’. This study was conducted to determine the structural requirements of CYP analogues necessary for antagonist activity and to examine the possibility that the agonist effects of CYP and its analogues may occur through a mechanism independent of β‐adrenoceptor activation. 2 Analogues of CYP and pindolol were tested for antagonist activity in rat ileum in which the β 1 ‐ and β 2 ‐adrenoceptors were blocked. Fourteen compounds were tested against (−)−isoprenaline, and four of the more potent analogues were then tested against BRL 37344. The two most potent antagonists were CYP and iodocyanopindolol. The p K b values (negative log of equilibrium dissociation constant) obtained against (−)−isoprenaline were significantly higher than those obtained against BRL 37344, but the cause of this difference is not known. 3 Several structural requirements were determined for antagonist activity. Modification at the carbon atom alpha to the secondary amine caused the antagonist potency to fall as the level of saturation was reduced. Thus, a quaternary carbon group, such as t ‐butyl, produced the most potent antagonist. Substitution with a large moiety such as a cyclohexyl or benzyl group reduced antagonist activity, probably due to steric hindrance. Inclusion of an electron‐withdrawing group, such as a cyano or ethylester moiety, alpha to the indole nitrogen, also increased the potency. Iodination of CYP and ethylesterpindolol at the 3‐position of the indole ring did not increase antagonist potency. In contrast, iodination of the almost inactive analogues produced a significant increase in potency, suggesting that a beneficial electronic effect on the indole ring imparted by the iodo moiety may be able to offset partially the negative effects caused by either the steric hindrance, of lack of a quaternary carbon alpha to the secondary amine. 4 Values for pseudo‐pD 2 were also determined by conducting cumulative concentration‐response studies up to the limit of drug solubility. For nine of the compounds tested, the p K b was significantly higher than the pseudo‐pD 2 value. 5 The discrepancy between the p K b and pseudo‐p D 2 values was examined further. The agonist effects of iodocyanopindolol, the agonist with the highest potency, were not antagonized by CYP which was the most potent antagonist of (−)−isoprenaline and BRL 37344 at the β 3 ‐adrenoceptor. This suggests that the agonist effects of iodoCYP were produced through a different mechanism: either via another receptor, another isoform of the rat β 3 ‐adrenoceptor, or through a non‐receptor‐mediated effect. Pseudo‐pD 2 values did not correlate with log P values for these compounds, indicating that their relaxant effects were not simply a function of their lipid solubility. 6 This study has highlighted several structural requirements for antagonist binding potency at the rat ileum β 3 ‐adrenoceptor and should assist in the development of potent selective antagonists for this receptor.