16 research outputs found
Slow dissociation of partial agonists from the D2 receptor is linked to reduced prolactin release.
In this study we investigated the correlation between affinity, efficacy, peripheral receptor occupancy, and kinetic properties of D2 dopamine receptor ligands with time-course evaluations of prolactin release in rat blood. We profiled typical and atypical antipsychotic antagonists at D2 receptors, the partial agonist aripiprazole, and four novel partial agonist compounds with different properties. Clozapine and quetiapine revealed lower prolactin release and fast dissociation kinetics, linking fast dissociation and prolactin sparing
properties. Surprisingly, haloperidol, a highly prolactin-releasing antagonist, shared intermediate dissociation properties. Factors other than kinetic properties may thus contribute to prolactin-releasing properties of antagonists. Partial agonists sharing similar efficacies and receptor occupancies differed markedly in their ability to induce hyperprolactinaemia. Aripiprazole moderately released prolactin even at high receptor occupancies, with slow dissociation from D2 receptors. Other compounds displaying low affinities and fast dissociations released prolactin substantially, although less than haloperidol. The effect augmented after repeated administrations. Compounds with high affinities and slow dissociation rates stimulated moderate prolactin release at high receptor occupancies, reaching a ceiling effect at 50\u201360% occupancy. Moreover, the effect developed tolerance. In conclusion, we investigated the affinity and kinetic properties of D2 partial agonists associated with their ability to induce prolactin release in blood. We propose that for D2 partial agonists, at comparable intrinsic activities and peripheral occupancies, the prolactin-releasing properties are linked to their kinetic rate properties. Differently from D2 antagonists, partial agonists display slow dissociation and high affinity associated with a low prolactin release profile
Evidence that the metabotropic glutamate receptor 5 antagonist MPEP may act as an inhibitor of the norepinephrine transporter in vitro and in vivo
2,4-Dicarboxy-pyrroles as Selective Non-Competitive mGluR1 Antagonists: an exploration of the role of the pyrrolic scaffold
Structure-activity studies on neuropeptide S - Identification of the amino acid residues crucial for receptor activation
Neuropeptide S (NPS) has been recently recognized as the
endogenous ligand for the previous orphan G-protein-coupled
receptor GPR154, now referred to as the NPS receptor
(NPSR). The NPS-NPSR receptor system regulates important
biological functions such as sleeping/wakening, locomotion,
anxiety, and food intake. To collect information on the mechanisms
of interaction between NPS and its receptor, a classical
structure-activity relationship study was performed.
Human (h) NPS derivatives obtained by Ala and D-scan and
N- and C-terminal truncation were assessed for their ability
to stimulate calcium release in HEK293 cells expressing the
human recombinant NPSR. The results of this study indicate
that (i) the effect of hNPS is mimicked by the fragment hNPS-
(1-10); (ii) Phe2, Arg3, and Asn4 are crucial for biological
activity; (iii) the sequence Thr8-Gly9-Met10 is important for
receptor activation, although with non-stringent chemical
requirements; and (iv) the sequence Val6-Gly7 acts as a hinge
region between the two above-mentioned domains. However,
the stimulatory effect of hNPS given intracerebroventricularly
on mouse locomotor activity was not fully mimicked by
hNPS-(1-10), suggesting that the C-terminal region of the
peptide maintains importance for in vivo activity. In conclusion,
this study identified the amino acid residues of this peptide
most important for receptor activation
Structure-activity studies on neuropeptide S - Identification of the amino acid residues crucial for receptor activation
Neuropeptide S (NPS) has been recently recognized as the
endogenous ligand for the previous orphan G-protein-coupled
receptor GPR154, now referred to as the NPS receptor
(NPSR). The NPS-NPSR receptor system regulates important
biological functions such as sleeping/wakening, locomotion,
anxiety, and food intake. To collect information on the mechanisms
of interaction between NPS and its receptor, a classical
structure-activity relationship study was performed.
Human (h) NPS derivatives obtained by Ala and D-scan and
N- and C-terminal truncation were assessed for their ability
to stimulate calcium release in HEK293 cells expressing the
human recombinant NPSR. The results of this study indicate
that (i) the effect of hNPS is mimicked by the fragment hNPS-
(1-10); (ii) Phe2, Arg3, and Asn4 are crucial for biological
activity; (iii) the sequence Thr8-Gly9-Met10 is important for
receptor activation, although with non-stringent chemical
requirements; and (iv) the sequence Val6-Gly7 acts as a hinge
region between the two above-mentioned domains. However,
the stimulatory effect of hNPS given intracerebroventricularly
on mouse locomotor activity was not fully mimicked by
hNPS-(1-10), suggesting that the C-terminal region of the
peptide maintains importance for in vivo activity. In conclusion,
this study identified the amino acid residues of this peptide
most important for receptor activation
Stereoselective synthesis and preliminary evaluation of (+)- and (-)-3-methyl-5-carboxy-thien-2-yl-glycine (3-MATIDA): identification of (+)-3-MATIDA as a novel mGluR1 competitive antagonist.
In vitro and in vivo pharmacological characterization of the novel UT receptor ligand [Pen(5), DTrp(7), Dab(8)] urotensin II(4-11) (UFP-803)
The novel urotensin-II (U-II) receptor (UT) ligand, [Pen(5),DTrp(7),Dab(8)]U-II(4-11) (UFP-803), was pharmacologically evaluated and compared with urantide in in vitro and in vivo assays. In the rat isolated aorta, UFP-803 was inactive alone but, concentration dependently, displaced the contractile response to U-II to the right, revealing a competitive type of antagonism and a pA(2) value of 7.46. In the FLIPR [Ca(2+)](i) assay, performed at room temperature in HEK293(hUT) and HEK293(rUT) cells, U-II increased [Ca(2+)](i) with pEC(50) values of 8.11 and 8.48. Urantide and UFP-803 were inactive as agonists, but antagonized the actions of U-II by reducing, in a concentration-dependent manner, the agonist maximal effects with apparent pK(B) values in the range of 8.45-9.05. In a separate series of experiments performed at 37 degrees C using a cuvette-based [Ca(2+)](i) assay and CHO(hUT) cells, urantide mimicked the [Ca(2+)](i) stimulatory effect of U-II with an intrinsic activity (alpha) of 0.80, while UFP-803 displayed a small (alpha=0.21) but consistent residual agonist activity. When the same experiments were repeated at 22 degrees C (a temperature similar to that in FLIPR experiments), urantide displayed a very small intrinsic activity (alpha=0.11) and UFP-803 was completely inactive as an agonist. In vivo in mice, UFP-803 (10 nmol kg(-1)) antagonized U-II (1 nmol kg(-1))-induced increase in plasma extravasation in various vascular beds, while being inactive alone. In conclusion, UFP-803 is a potent UT receptor ligand which displays competitive/noncompetitive antagonist behavior depending on the assay. While UFP-803 is less potent than urantide, it displayed reduced residual agonist activity and as such may be a useful pharmacological tool