Academic literature on the topic 'Iodocyanopindolol'

1. We have studied the effect of the anti-inflammatory anti-asthma drug, nedocromil sodium, on down-regulation of pulmonary β-adrenoceptors in guinea-pig lung. 2. Incubation of minced lung with isoprenaline (10 μmol/l) resulted in a reduction in maximum binding capacity of [125I]iodocyanopindolol to lung membranes from 246 ± 4 to 169 ± 6 fmol/mg of protein (mean ± sem, P < 0.01, n = 18). 3. Nedocromil sodium, which had no direct effect on [125I]iodocyanopindolol binding, prevented isoprenaline-induced down-regulation, giving complete protection at a dose of 100 μmol/l. 4. The mechanism of this effect is not certain, but nedocromil sodium may interfere with the internalization of β-adrenoceptors in pulmonary parenchymal cells. This may have some therapeutic relevance.

The beta-adrenergic receptor adenylate cyclase system of ventricular tissue was evaluated in a group of rats submitted to a progressive 10-wk running program on a treadmill and compared with that in a group of rats maintained sedentary during the same period. Adequate training was confirmed by a 46% increase in the gastrocnemius isocitrate dehydrogenase activity in the trained group [1.50 +/- 0.04 vs. 1.03 +/- 0.06 (SE) pmol.g-1.min-1; P less than 0.01). Binding studies with [125I]iodocyanopindolol showed a 13% reduction in the density of beta-adrenergic receptors in trained rats (42.6 +/- 2.1 vs. 49.0 +/- 2.1 fmol/mg; P less than 0.05) without any significant modification in the dissociation constant. The amount of [125I]iodocyanopindolol bound to beta-adrenoceptors in the high-affinity state was reduced by 16.6% in trained rats (12.5 +/- 0.9 vs. 15.0 +/- 0.5 fmol/mg; P less than 0.05) without any significant changes for those in the low-affinity state, indicating a decrease in the coupling between the beta-adrenergic receptors and the guanine stimulatory binding protein. Furthermore, although the basal and sodium fluoride-stimulated adenylate cyclase activities were similar in the two groups of rats, the response of adenylate cyclase maximally stimulated by 10(-5) M isoproterenol was reduced by 16% in trained rats (29.7 +/- 1.4 vs. 35.3 +/- 1.3 pmol.mg-1.min-1; P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Proximal tubules were isolated from the rat kidney by collagenase digestion of the cortical tissue followed by Percoll gradient centrifugation. Microscopic and hormone-stimulated adenylate cyclase activity studies proved the purity of the preparation. [3H]Prazosin, [3H]rauwolscine, and [125I]iodocyanopindolol were used to identify and quantitate respectively the alpha 1-, alpha 2- and beta-adrenergic receptors. Proximal tubular (F4) particulate fraction was compared against other cortical nephron segment (F1, F2) fractions and the total collagenase-digested cortex particulate suspension (Ft). Proximal tubules were enriched in alpha 1- and alpha 2-adrenergic receptors compared with Ft (alpha 1-receptor, 100.4 +/- 4.5 vs. 87.4 +/- 4.9; alpha 2-receptor, 250 +/- 16.2 vs. 185.1 +/- 12 fmol/mg protein). The fractions enriched in glomeruli and distal tubular segments (F1, F2) had relatively low concentrations of alpha 1- and alpha 2-adrenergic receptors. In contrast, beta-adrenergic receptor concentration in the proximal tubules was approximately 25% of that in the Ft fraction and approximately 10% of that in the F1 fraction. Isoproterenol-stimulated adenylate cyclase activities in the different fractions corroborated well with the pattern suggested by the [125I]iodocyanopindolol binding studies. Our results suggest that whole-cortex preparation radioligand binding studies may reflect proximal tubular alpha 1- and alpha 2-adrenergic receptor changes quite well. They may, however, miss or give erroneous impressions about beta-adrenergic receptor changes occurring in different cortical nephron segments.

The B3-adrenoceptor (B-AR) was first classified in 1984 in rat brown adipose tissue. The classification of this receptor in other tissues and species is hampered by the lack of selective B3-antagonists which, despite the identification of further classes of B3-agonist ligands, remains elusive. In this study, a series of novel B3-AR antagonist drugs were synthesised and their pharmacological profile in rat ileum investigated with the aim of increasing our understanding of the structural requirements of drug-receptor binding in B3-ARs. Analogues of iodocyanopindolol (ICYP) (17) and conformationally impaired analogues of BRL 37344 were identified as key synthetic targets.

ICYP and eleven analogues were synthesised from epoxide precursor (38). The pharmacological activity of these compounds was determined in a rat ileum preparation with tissue contraction solely due to the B3-AR. All ICYP analogues were active at the B3-AR. The pharmacological data revealed: (i) of the analogues tested, ICYP (17) and CYP (18) had the highest affinities at the B3-AR. This is in sharp contrast to the binding of ICYP (17) and CYP (18) at B1- and B2-ARs where ICYP (17) has a hundred fold higher affinity than CYP (18); and (ii) two pharmacological characteristics determined for the drugs, namely pD2 and the pKb, were significantly different for eight of the analogues studied. These drugs were partial agonists, and the discrepancy between pD2 and pKb values indicated binding to more than one receptor population.

Three hypotheses were proposed to explain this observation; (i) two different B3-ARs are present; (ii) the result is an enantiomeric effect; and (iii) the difference is a non-specific lipophilic effect.

Log P values for the series were determined using HPLC, and no correlation was found between Log P and pD2 or pKb values.

To examine the second hypothesis, both enantiomers of CYP (18) and bupranolol (8) were synthesised and their pharmacological activity investigated in rat ileum. All four enantiomers tested were antagonists at the B3-AR, with the receptor displaying stereoselectivity for the (S)-enantiomers, with (S)-CYP (18b) being the most potent B3-antagonist drug identified. Examination of the partial agonist activity of CYP and bupranolol enantiomers suggested that this effect was independent of the mechanism of B3-antagonism. The partial agonist effect was selective for (R)-CYP (18a) and non-selective for bupranolol. This result clearly defines (S)-CYP (18b) as a potent B3-AR antagonist and highlights structure-activity studies of CYP analogues as an important new source of information for the design of new classes of B3-antagonist drugs.

To further investigate the structure-function relationship being developed for B3-AR selective drugs the "extended conformation" hypothesis of Blin and co-workers was examined. These researchers proposed that the discrepancies observed between the B3-AR activity, and the B1/B2-AR activity of known agonist and antagonist drugs resulted from the ability of B3-agonist drugs to adopt an extended conformation at the B3-AR. To investigate this postulate, conformationally impaired analogues of the B3-AR agonist BRL 37344 (6) were targeted for synthesis. Allylic amine (112) was identified as a key precursor for conformationally impaired BRL 37344 analogues and was synthesised with solely (E) geometry from (d)-Bocalinal (109) and 4-methoxy benzylphosphonium chloride (111). Progress in the synthesis of other subtargets is described.