Characteristics of cyanopindolol analogues active at the β3‐adrenoceptor in rat ileum

• Published in: British journal of pharmacology 1996-10, Vol.119 (3), p.564-568
• Main Authors: Hoey, Andrew J., Jackson, Clifford M., Pegg, Graham G., Sillence, Martin N.
• Format: Article
• Language: English
• Subjects: atypical receptor; Biological and medical sciences; Catecholaminergic system; cyanopindolol; iodocyanopindolol; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Pindolol; rat ileum; β3‐adrenoceptors
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1996.tb15709.x

1 Cyanopindolol (CYP) is a potent antagonist at the β3‐adrenoceptor in rat ileum. Several analogues of CYP and pindolol were synthesized that also produced antagonist effects at the β3‐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 β1‐ and β2‐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 pKb 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‐pD2 were also determined by conducting cumulative concentration‐response studies up to the limit of drug solubility. For nine of the compounds tested, the pKb was significantly higher than the pseudo‐pD2 value. 5 The discrepancy between the pKb and pseudo‐pD2 values was examined further. The agonist effects of iodocyanopindolol, the agonist with