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Interactions of isamoltane (CGP 361A), an anxiolytic phenoxypropanolamine derivative, with 5-HT1, receptor subtypes in the rat brain

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Summary

Isamoltane (CGP 361A; (1-(2-(1-pyrrolyl)phenoxy)-3-isopropylamino-2-propanol hydrochloride), β-adrenoceptor ligand (IC50 = 8.4 nmol/l) which has reported activity as an anxiolytic in man was found to be a reasonably active inhibitor of the binding of [125I]ICYP to 5-HT1B recognition sites in rat brain membranes with 27-fold selectivity (IC50 = 39 nmol/l) as compared to the inhibition of binding of [3H]8-OH-DPAT to 5-HT1A receptors (IC50 = 1070 nmol/l). This selectivity was considerably greater than that observed for other β-adrenoceptor ligands including propranolol (5-HT1A/5-HT1B ratio = 2), oxprenolol (3.5) and cyanopindolol (8.7). The 5-HT1B activity of the compound resided in the (−)-enantiomer. (−)Isamoltane had weak activity (IC50 3–10 μmol/l) at 5-HT2 and α1-adrenoceptors. The compound was devoid of activity at a number of other central neurotransmitter recognition sites including the 5-HT1C site. Isamoltane increased the electrically evoked release of [3H]5-HT from prelabeled rat cortical slices in a manner similar to that of cyanopindolol. While both compounds were similar in potency to methiothepin, they had lower efficacy. Oxprenolol was less potent that both isamoltane and cyanopindolol while propranolol was essentially inactive. The effects of the compounds on 5-HT release appeared to be correlated with their 5-HT1B rather than 5-HT1A activity. In vivo, isamoltane increased 5-HTP accumulation in rat cortex following central decarboxylase inhibition at doses of 1 and 3 mg/kg i. p. At higher doses this effect was gradually diminished. Similar, but less clearcut results were obtained with cyanopindolol and oxprenolol, but propranolol was ineffective. No changes in brain tryptophan levels were associated with the isamoltaneevoked changes in brain 5-HTP levels. In reserpinized animals, isamoltane reduced 5-HTP accumulation even at doses which enhanced accumulation of this metabolite when given alone. The effects of the putative 5-HT1B agonist, m-trifluoromethylphenylpiperazine (TFMPP), the mixed 5-HT autoreceptor agonist/antagonist/ β-adrenoceptor antagonist, pindolol, the 5-HT uptake inhibitor, CGP 6085A and the MAO-A inhibitor, brofaromine, were not antagonized by pretreatment with isamoltane. The possibility that isamoltane and the other β-adrenoceptor antagonists are antagonists at 5-HT1B receptors and that their effect on 5-GT synthesis in vivo is the net result of their agonist/antagonist effects at 5-HT1A and 5-HT1B receptors is discussed in relation to the potential mechanism of the anxiolytic activity of isamoltane.

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Abbreviations

5-HT:

Serotonin

ICYP:

Iodocyanopindolol

8-OHDPAT:

8-hydroxy-2(di-n-propylamino) tetralin

TFMPP:

m-trifluoromethylphenylpiperazine

MAO-A:

monoamine oxidase-A

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Authors and Affiliations

  1. Research Department, Pharmaceuticals Division, K-125.607, CIBA-Geigy, CH-4002, Basel, Switzerland

    Peter C. Waldmeier, Peter A. Baumann & Serge Bischoff

  2. Summit, 07901, New Jersey, USA

    Michael Williams, Matthew A. Sills & Robert F. Neale

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  1. Peter C. Waldmeier
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  2. Michael Williams
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Waldmeier, P.C., Williams, M., Baumann, P.A. et al. Interactions of isamoltane (CGP 361A), an anxiolytic phenoxypropanolamine derivative, with 5-HT1, receptor subtypes in the rat brain. Naunyn-Schmiedeberg's Arch Pharmacol 337, 609–620 (1988). https://doi.org/10.1007/BF00175785

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