Terguride as a New Anti-Hyperprolactinemic Agent: Characterization in Rats and Dogs in Comparison with Bromocriptine

Abstract

ABSTRACT-Terguride, a derivative of the ergot alkaloid, was characterized as a new anti-hyperprolactin emic agent in rats and dogs in comparison with bromocriptine. Terguride was found to bind selectively to the pituitary dopamine D2-receptors with a high affinity (Kd=0.39 nM). In reserpinized rats, terguride at 0.03 mg/kg, p.o. significantly reduced the serum prolactin (PRL) level. The PRL lowering effect and the effective dose were longer lasting and about 30 times lower than those of bromocriptine, respectively. In rats bearing estrogen-induced pituitary prolactinoma, chronic terguride induced shrinkage of the prolactinoma as well as reduction of the high serum PRL level. In lactating rats, terguride (1.0 mg/kg, s.c.) reduced milk production in the mammary gland, whereas bromocriptine showed no significant effect up to 10 mg/kg, s.c. Terguride (10 mg/kg, p.o.) did not induce any stereotypy and hypermotility in reserpinized rats, while bromocriptine induced both stereotypy and hypermotility significantly at 10 mg/kg, p.o. In dogs, terguride, like bromocriptine, reduced the serum PRL level, but did not affect the serum levels of growth hormone and luteinizing hormone. In dogs, bromocriptine induced both emesis and PRL-lowering at almost the same dose, whereas emesis-inducing doses of terguride were about 100 times higher than the PRL-lowering dose. These results suggest that terguride as a dopamine D2-agonist is a potent inhibitor of PRL secretion with less neurotropic side effects compared to bromocriptine, and thus a useful drug for the treatment of galactor rhea and hyperprolactinemia including prolactinoma.Keywords: Terguride, Bromocriptine, Anti-hyperprolactinemic agent, Dopamine D2-agonist, Emetic action Dopamine (DA) D2-agonists, belonging to the family of ergot-derived drugs such as bromocriptine and lisu ride, are well known to be useful for the treatment of disorders characterized by hypersecretion of prolactin (PRL), such as galactorrhea and prolactinoma (1, 2). Bromocriptine, being the most widely utilized, has been shown not only to reduce the high PRL level in patients bearing prolactinoma and in postpartum women, but also to induce shrinkage of the tumor mass and reduction of lactation. However, such treatment is often associated with neurotropic side effects such as nausea and vomiting, which may be due to the D2-agonistic action on the cen tral dopaminergic systems; and as a result, about 10% of the patients discontinued the treatment (3 5). Thus, the drug development in this field recently has been directed to the search for a potent anti-hyperprolactinemic drug without the unwanted neurotropic side effects. Terguride, a 9,10-transdihydrogenated derivative of the ergot alkaloid lisuride, has been reported to exhibit both agonistic and antagonistic pharmacological effects at the DA D2-receptors depending upon the location and the state of the receptors (6-9). Like D2-agonists, terguride inhibits hypersecretion of PRL in reserpinized rats at low doses, suggesting a potent agonistic action on the...

Effects of dopamine d2 receptor agonists in a pituitary transplantation‐induced hyperprolactinaemia/anovulation model in rats

“…These results are consistent with the experience obtained so far with these drugs in hyperprolactinaemic patients 11,12 and with the results of a comparative study in rats. The difference between our results and those of Mizokawa et al 20 may be a consequence of the different hyperprolactinaemic model and/or bleeding point used. In contrast, Mizokawa et al 20 have reported that the inhibitory effect of terguride on prolactin secretion lasted longer than that of bromocriptine.…”

“…Moreover, cabergoline had a longer-lasting effect than the other two drugs, because it was still effective 5 days after its administration, whereas the effects of terguride and bromocriptine lasted only 3 days. In contrast, Mizokawa et al 20 have reported that the inhibitory effect of terguride on prolactin secretion lasted longer than that of bromocriptine. 33 In the present study, the rank order of these drugs with respect to their duration of action on prolactin secretion was as follows: cabergoline > terguride ϭ bromocriptine.…”

“…33 In the present study, the rank order of these drugs with respect to their duration of action on prolactin secretion was as follows: cabergoline > terguride ϭ bromocriptine. In contrast, Mizokawa et al 20 have reported that the inhibitory effect of terguride on prolactin secretion lasted longer than that of bromocriptine. The difference between our results and those of Mizokawa et al 20 may be a consequence of the different hyperprolactinaemic model and/or bleeding point used.…”

“…In contrast, Mizokawa et al 20 have reported that the inhibitory effect of terguride on prolactin secretion lasted longer than that of bromocriptine. The difference between our results and those of Mizokawa et al 20 may be a consequence of the different hyperprolactinaemic model and/or bleeding point used. Regardless, it is clear that cabergoline has a longer-lasting effect than either terguride or bromocriptine.…”

“…Although the majority of patients can tolerate the chronically effective doses of bromocriptine, side effects, including nausea, dizziness, headache and vomiting, are common. 18 A few years ago, terguride was developed as a new prolactin-lowering drug, 19,20 but due to its relatively short duration of action it, too, has to be administered twice a day. 21 In endocrinological studies, the transplantation of anterior pituitaries under the kidney capsule is known to induce hyperprolactinaemia in rats.…”