New Serotonin 5-HT_1A Receptor Agonists Endowed with Antinociceptive Activity in Vivo

Abstract

We report the synthesis of new compounds 4-35 based on two different openings (A and B) of the chromane ring present in the previously identified 5-HT1A receptor (5-HT1AR) ligand 3. The synthesized compounds were assessed for binding affinity, selectivity, and functional activity at the 5-HT1AR. Selected candidates resulting from B opening were also evaluated for their potential antinociceptive effect in vivo and pharmacokinetic properties in vitro. Analogue 19 [2-(4-{[2-(2-ethoxyphenoxy)ethyl]amino}butyl)tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione] has been characterized as a high-affinity and potent 5-HT1AR agonist (Ki = 2.3 nM; EC50 = 19 nM). Pharmacokinetic studies indicated that compound 19 displays a good metabolic stability in human liver microsomes (t1/2 ∼ 3 h and CLint = 3.5 mL/min/kg, at 5 μM), and a low level of protein binding (25%, at 5 μM). Interestingly, 19 (3 mg/kg, ip, and 30 mg/kg, po) caused significant attenuation of formalin-induced behavior in early and late phases of the mouse intradermal formalin test of pain, and this in vivo effect was reversed by the selective 5-HT1AR antagonist WAY-100635. Thus, the new 5-HT1AR agonist identified in this work, 19, exhibits oral analgesic activity, and the results herein represent a step toward identifying new therapeutics for the control of pain.

Platelet Derivatives in Regenerative Medicine: An Update

“…Reduction in pain was attributed to release of serotonin by platelet dense granules [79] or the activity of recruited leukocytes [80]. Non-randomized favorable results have been reported in the treatment of osteoarthritis [81,82] and sports medicine [83][84][85].…”

7-Amino-2-phenylpyrazolo[4,3-d]pyrimidine derivatives: Structural investigations at the 5-position to target human A1 and A2A adenosine receptors. Molecular modeling and pharmacological studies

“…The 5-(3-arylpropyl)-substituted pyrazolopyrimidine derivatives 25e28 were obtained by reacting 34 with ammonium acetate and the ethyl arylbutanimidate hydrochlorides 37 [44] and 38e40 (Scheme 3). These latter were prepared from the corresponding 3-arylpropylnitriles [45,47] and hydrochloric acid in absolute ethanol. Finally, compound 31 was O-alkylated with allyl and benzyl chlorides to yield derivatives 32 and 33, respectively.…”

5-HT_1A Receptors Mediate Analgesia Induced by Emulsified Sevoflurane in Thermal Nociception but Have Little Effect on Chemical Nociception

“…5-HT 1A Rs are involved in a variety of physiological functions such as sleep, excitement, feeding, body temperature regulation, pain, and emotional and cognitive regulation [33,34]. Activation of 5-HT 1A Rs inhibits acute and chronic pain [35,36]. The relationship between 5-HT 1A R and pain focuses mainly on neuropathic pain.…”