Imidazoline 1 receptor activation preserves respiratory drive in spontaneously breathing newborn rats during dexmedetomidine administration.

BACKGROUND: Dexmedetomidine is an alpha-2 (α2 ) adrenoceptor and imidazoline 1 (I1 ) receptor agonist that provides sedation without loss of respiratory drive. AIMS: The aim of this study was to elucidate the involvement of α2 -adrenoceptor and I1 receptor in the cardiorespiratory changes induced by dexmedetomidine in spontaneously breathing newborn rats. METHODS: An abdominal catheter to administer drugs and three subcutaneous electrodes to record electrocardiographic data were inserted into 2- to 5-day-old Wistar rats under isoflurane anesthesia. In individual chambers, each rat was intraperitoneally administered dexmedetomidine (50 µg·kg-1 ) followed 5 min later by normal saline or 1, 5, or 10 mg·kg-1 atipamezole (selective α2 -adrenoceptor antagonist) or efaroxan (α2 -adrenoceptor/I1 receptor antagonist). Cardiorespiratory indices were recorded before and after drug administration. RESULTS: The administration of dexmedetomidine alone resulted in significant changes to most of the cardiorespiratory indices examined. The addition of 5 or 10 mg·kg-1 atipamezole or 1 mg·kg-1 efaroxan completely ameliorated the dexmedetomidine-associated reduction in heart rate (HR). The addition of 1 mg·kg-1 atipamezole or 1 or 5 mg·kg-1 efaroxan completely ameliorated the dexmedetomidine-associated reduction in respiratory frequency. Mean inspiratory flow (VT /TI ; VT is tidal volume and TI is inspiratory time), which is an index of respiratory drive, was not significantly affected by the administration of dexmedetomidine alone (P = 0.273) or dexmedetomidine + atipamezole (P = 0.605, 0.153, 0.138 for 1, 5, 10 mg·kg-1 atipamezole, respectively); however, it was significantly decreased after the administration of dexmedetomidine + efaroxan (P = 0.029, <0.001, <0.001 for 1, 5, 10 mg·kg-1 efaroxan, respectively). CONCLUSIONS: Our results suggest that in newborn rats undergoing dexmedetomidine sedation, the α2 -adrenoceptor, but not I1 receptor, is involved in the regulation of HR and respiratory frequency, and that activation of the I1 receptor plays a major role in the maintenance of respiratory drive.

Effects of dexmedetomidine on cardiorespiratory regulation in spontaneously breathing newborn rats.

BACKGROUND: Dexmedetomidine, a selective α2-adrenoceptor agonist, is a new sedative agent. OBJECTIVE: To examine the dexmedetomidine-associated changes in cardiorespiratory indices in spontaneously breathing newborn rats. METHODS: An abdominal catheter to administer drugs and subcutaneous electrodes to record electrocardiographic data were inserted into 2- to 4-day-old rats under isoflurane anesthesia; the rats were then placed in individual chambers. After recovery from the anesthesia, the rats received intraperitoneal administrations of normal saline (NS, vehicle), dexmedetomidine (50 µg·kg(-1)), or dexmedetomidine (50 µg·kg(-1)) followed 5 min later with NS or the selective α2-adrenoceptor antagonist atipamezole (1 mg·kg(-1)) (n = 10 in each group). Cardiorespiratory indices were recorded for each animal throughout the experiment. RESULTS: Dexmedetomidine administration significantly decreased heart rate (HR) and minute ventilation (V'E) (P < 0.05) compared with control, whereas NS administration did not. The decrease in HR and V'E after dexmedetomidine administration was significantly less in rats that received atipamezole (P < 0.05) than in those that received NS after dexmedetomidine administration. The dexmedetomidine-associated V'E depression was attributed to a significant decrease in respiratory frequency (fR) but not tidal volume (VT ). The change in fR was reversed by atipamezole administration, which itself induced no significant changes in HR and fR. CONCLUSION: In spontaneously breathing immature rats, dexmedetomidine administration significantly reduced HR and V'E. Because atipamezole fully reversed decreases in fR and therefore V'E, dexmedetomidine-related respiratory suppression occurs predominantly through α2-adrenoceptor-related suppression of fR.

Identification of 1S,2R-milnacipran analogs as potent norepinephrine and serotonin transporter inhibitors.

A series of milnacipran analogs were synthesized and studied as monoamine transporter inhibitors, and several potent compounds with moderate lipophilicity were identified from the 1S,2R-isomers. Thus, 15l exhibited IC(50) values of 1.7nM at NET and 25nM at SERT, which were, respectively, 20- and 13-fold more potent than 1S,2R-milnacipran 1-II.

Studies on the SAR and pharmacophore of milnacipran derivatives as monoamine transporter inhibitors.

Derivatives of milnacipran were synthesized and studied as monoamine transporter inhibitors. Potent analogs were discovered at NET (9k) and at both NET and SERT (9s and 9u). A pharmacophore model was established based on the conformational analysis of milnacipran in aqueous solution using NMR techniques and was consistent with the SAR results.

Studies on the structure-activity relationship of bicifadine analogs as monoamine transporter inhibitors.

Compounds with various activities and selectivities were discovered through structure-activity relationship studies of bicifadine analogs as monoamine transporter inhibitors. The norepinephrine-selective 2-thienyl compound S-6j was efficacious in a rodent pain model.

Studies on a series of milnacipran analogs containing a heteroaromatic group as potent norepinephrine and serotonin transporter inhibitors.

A series of milnacipran analogs containing a heteroaromatic group were synthesized and studied as monoamine transporter inhibitors. Many compounds exhibited higher potency than milnacipran at NET and NET/SERT with no significant change in lipophilicity. For example, compound R-26f was about 10-fold more potent than milnacipran with IC(50) values of 8.7 and 26nM at NET and SERT, respectively.

A thienopyridazinone-based melanin-concentrating hormone receptor 1 antagonist with potent in vivo anorectic properties.

Melanin-concentrating hormone receptor antagonists containing thieno- and a benzopyridazinone cores were designed and tested as potential anorectic agents. These ligands showed high affinity for the receptor, potent functional activity in vitro, and good oral bioavailabilty in rats. The thiophene analogue exhibited low iv clearance, long half-life, and high brain penetration. In obese rats, the thienopyridazinone demonstrated a dose-dependent reduction in feeding and body weight with doses between 1 and 10 mg kg-1.

Characterization of thien-2-yl 1S,2R-milnacipran analogues as potent norepinephrine/serotonin transporter inhibitors for the treatment of neuropathic pain.

Thien-2-yl 1S,2R-milnacipran analogues were synthesized and characterized as norepinephrine/serotonin transporter inhibitors. These compounds possessed higher potencies than 1S,2R-milnacipran (2R-1) while maintaining low molecular weight and moderate lipophilicity, which are the important features for the pharmacological and pharmacokinetic characteristics of milnacipran (1). Thus, compound 5c exhibited IC50 values of 2.3 and 32 nM, respectively, at NET and SERT, which were more than 10-fold better than those of 1 (NET IC50 = 77 nM, SERT IC50 = 420 nM). Moreover, 5c achieved the same efficacy as 1, but with much lower doses, in a rodent spinal nerve ligation pain model. In addition, 5c displayed desirable pharmacokinetic properties in several species, including high oral availability and significant brain penetration.

Thienopyrimidinone bis-aminopyrrolidine ureas as potent melanin-concentrating hormone receptor-1 (MCH-R1) antagonists.

A series of thienopyrimidinone bis-aminopyrrolidine ureas were designed, synthesized, and evaluated for their ability to bind melanin-concentrating hormone receptor-1. These compounds exhibit potent binding affinity (K(i)=3 nM) and good in vitro metabolic stability.

Synthesis and structure-activity relationships of spirohydantoin-derived small-molecule antagonists of the melanin-concentrating hormone receptor-1 (MCH-R1).

The design, synthesis, and SAR of a series of substituted spirohydantoins are described. Optimization of an in-house screening hit gave compounds that exhibited potent binding affinity and functional activity at MCH-R1.

Substituted chromones and quinolones as potent melanin-concentrating hormone receptor 1 antagonists.

A series of substituted chromones were designed, synthesized, and evaluated for their ability to bind melanin-concentrating hormone receptor 1. Compounds with subnanomolar binding affinity and 66% oral bioavailability in rats were discovered.

Synthesis and structure-activity relationships of retro bis-aminopyrrolidine urea (rAPU) derived small-molecule antagonists of the melanin-concentrating hormone receptor-1 (MCH-R1). Part 1.

The design, synthesis, and SAR of a series of retro bis-aminopyrrolidine ureas are described. Compounds from this series exhibited potent binding affinity and functional activity at MCH-R1, and good oral bioavailability in rat.

Bis(aminopyrrolidine)-derived ureas (APUs) as potent MCH1 receptor antagonists.

Ureas derived from two substituted 3-aminopyrrolidine subunits were prepared as constrained analogs of a linear lead compound and tested as antagonists of the MCH(1) receptor. The series was optimized for substitution and stereochemistry to generate a functional antagonist with a K(i) of 3.3 nM and IC(50) of 12 nM (GTPgammaS).

Synthesis and structure-activity relationships of biarylcarboxamide bis-aminopyrrolidine urea derived small-molecule antagonists of the melanin-concentrating hormone receptor-1 (MCH-R1).

A novel series of bis-aminopyrrolidine ureas containing either a 4-biphenylcarboxmide or 5-phenyl-2-thiophenecarboxamide group have been identified as potent and functional antagonists of the melanin-concentrating hormone receptor-1. Syntheses and SAR are described, which led to the discovery of compounds with high binding affinity (Ki = 1 nM) for the receptor. Preliminary in vitro metabolic stability data are also reported for key compounds.