Allosteric alpha 1-adrenoreceptor antagonism by the conopeptide rho-TIA.

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Sharpe IA, Thomas L, Loughnan M, Motin L, Palant E, Croker DE, Alewood D, Chen S, Graham RM, Alewood PF, Adams DJ, Lewis RJ

Allosteric alpha 1-adrenoreceptor antagonism by the conopeptide rho-TIA.

J Biol Chem. 2003 Sep 5;278(36):34451-7. Epub 2003 Jun 24.

PubMed ID

12824165 [ View in PubMed

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Abstract

A peptide contained in the venom of the predatory marine snail Conus tulipa, rho-TIA, has previously been shown to possess alpha1-adrenoreceptor antagonist activity. Here, we further characterize its pharmacological activity as well as its structure-activity relationships. In the isolated rat vas deferens, rho-TIA inhibited alpha1-adrenoreceptor-mediated increases in cytosolic Ca2+ concentration that were triggered by norepinephrine, but did not affect presynaptic alpha2-adrenoreceptor-mediated responses. In radioligand binding assays using [125I]HEAT, rho-TIA displayed slightly greater potency at the alpha 1B than at the alpha 1A or alpha 1D subtypes. Moreover, although it did not affect the rate of association for [3H]prazosin binding to the alpha 1B-adrenoreceptor, the dissociation rate was increased, indicating non-competitive antagonism by rho-TIA. N-terminally truncated analogs of rho-TIA were less active than the full-length peptide, with a large decline in activity observed upon removal of the fourth residue of rho-TIA (Arg4). An alanine walk of rho-TIA confirmed the importance of Arg4 for activity and revealed a number of other residues clustered around Arg4 that contribute to the potency of rho-TIA. The unique allosteric antagonism of rho-TIA resulting from its interaction with receptor residues that constitute a binding site that is distinct from that of the classical competitive alpha1-adrenoreceptor antagonists may allow the development of inhibitors that are highly subtype selective.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Prazosin	Alpha-1B adrenergic receptor	Protein	Humans	Yes	Antagonist	Details