Prostaglandin receptors on human platelets. Structure-activity relationships of stimulatory prostaglandins

Abstract

1. Synthetic analogues of prostaglandins E2 or F2a, (monocyclic bisenoic prostaglandins), like the endogenous prostaglandin endoperoxides (prostaglandins G2 and H2) from platelets, and like synthetic analogues of prostaglandin H2 (bicyclic bisenoic prostaglandins), can induce aggregation of human platelets, although prostaglandins E2 and F2. themselves are inactive. 2. All the prostanoid compounds that induce platelet aggregation release 5-hydroxytryptamine from platelet dense bodies, but do not release f6-Nacetylglucosaminidase from lysosomal granules. Arachidonic acid evokes a similar response. 3. All endoperoxide analogues tested (bicyclic compounds) were powerful platelet stimulants, and all active compounds (whether mono-or bi-cyclic) apparently acted via the same receptor as the endogenous prostaglandin endoperoxides. 4. The nature and stereospecificity of substituents at positions 11 and 15 (or 16) on prostaglandin E2 are critical determinants for platelet-stimulating activity: deoxy substitution at position 11 plus methylation at position 15 (or 16) produces a potent stimulant, particularly if the groups around C-1 5 are in the S configuration. 5. The effects of these structural modifications are apparently due to, at least in part, a change in side-chain conformation.The formation of platelet aggregates and the associated secretion of platelet constituents, reactions of great importance in haemostasis and thrombosis, are influenced by prostaglandins and related compounds formed by the platelets in response to stimuli and also when these compounds are added exogenously (Kloeze, 1967;Willis, 1974;Samuelsson et al., 1976). The main precursor ofthe prostaglandins formed by most cell types (including platelets) is arachidonic acid, and its metabolic products have important and diverse effects on many cells, but with the notable exception of the corpus luteum (Powell et al., 1975), the receptors that mediate these effects have not yet been well characterized. The platelet provides a valuable cellular model for studying such prostaglandin receptors. The prostaglandin endoperoxides G2 and H2 are potent platelet stimulants (Hamberg et al., 1974;Willis et al., 1974), as is their major metabolic product, thromboxane A2 (Hamberg et al., 1975;Needleman et al., 1976). The study of these compounds is complicated by their lability in aqueous media, but analysis of their actions has been facilitated by the recent synthesis of stable analogues of prostaglandin H2 (Corey et al., 1975;Bundy, t Present address:

Activation of Human Blood Platelets Induced by Nocloprost, a Stable Prostaglandin E₂ Derivative

“…Our results are in agreement with those reported by MacIntyre et al [ 15]. Méth ylation of PGE2 at position C-15 or C-16 and substitution at C-9 led to substances with stimulatory activity on platelets at concentra tions up to 0.1 pmol/1 while PGE2 was inac tive.…”

“…After oral application of misoprostol, a 16-methyl derivative of PGE1; at doses used for gastric antiulcer therapy no changes of plate let function and bleeding time were found [14]. However, in vitro studies on human platelets have shown that PGEj derivatives with methylation at position 15 or 16 are able to induce aggregation and secretion [15].…”

EFFECTS OF RP AND SP DIASTEREOISOMERS OF ADENOSINE 5′‐O‐(1‐THIODIPHOSPHATE) ON HUMAN PLATELETS

“…This inhibitory action of each diastereoisomer could have been due either to the appearance at high concentrations of a separate inhibitory effect not specific for ADP, or to a low efficacy at the ADP receptor. No inhibitory action was found when platelets were aggregated in the presence of either diastereoisomer by 11,9-epoxymethano PGH2 ( Figure Id), which acts at a prostaglandin receptor (MacIntyre, Salzman & Gordon, 1978), and our evidence therefore suggests that (R)-ADP-a-S and (S)-ADPa-S are partial agonists, each with an intrinsic activity of 0.75, at the ADP receptor mediating aggregation of human platelets. This behaviour is similar to that of adenosine 5'-O-(2-thiodiphosphate) (ADP-,8-S), an ADP analogue in which a terminal (,3) phosphate oxygen is replaced by sulphur, which is also a partial agonist with an intrinsic activity of 0.75 as an aggregating agent (Cusack & Hourani, 1981).…”

Modulation of Platelet Function by Prostaglandins: Characterization of Platelet Receptors for Stimulatory Prostaglandins and the Role of Arachidonate Metabolites in Platelet Degranulation Responses

“…After addition of an agonist to the stirred samples, reactions were terminated by adding 4 vol ice-cold 0.4% w/v EDTA in iso-osmotic saline, and immediate centrifugation (14,700 g; 20 °C; 1 min). Subsamples of cell free supernatant were taken for fluorimetric measurement of (3-N-acetyl-glucosaminidase (/3-NAG, a platelet lysosomal en zyme) and for radio-isotopic determination of (14C|-5-HT (a platelet-dense granule consti tuent), as described previously (31). A further subsample was taken for radioimmunoassay of (3-thromboglobulin (/3-TG, a platelet alpha granule constituent) (32).…”