New 1-(heterocyclylalkyl)-4-(propionanilido)-4-piperidinyl methyl ester and methylene methyl ether analgesics

Abstract

A series of new 1-(heterocyclyalkyl)-4-(propionanilido)-4-piperidinyl methyl esters and methylene methyl ethers have been synthesized and pharmacologically evaluated. In the mouse hot-plate test, the majority of compounds exhibited an analgesia (ED50 less than 1 mg/kg) superior to that of morphine. These studies revealed a pharmacological accommodation for many more structurally diverse and far bulkier aromatic ring systems than the corresponding components of the arylethyl groups of the prototypic methyl ester (carfentanil, 2) and methylene methyl ether (sufentanil, 3 and alfentanil, 4) 4-propionanilido analgesics. Compound 9A (methyl 1-[2-(1H-pyrazol-1-yl)-ethyl]-4-[(1-oxopropyl)phenylamino]-4- piperidinecarboxylate), which exhibited appreciable mu-opioid receptor affinity, was a more potent and short-acting analgesic, than alfentanil with less respiratory depression in the rat. On the other hand, the phthalimides 57A and 57B, which exhibited negligible affinity for opioid receptors associated with the mediation of nociceptive transmission (i.e., mu-, kappa-, and delta-subtypes), displayed analgesic efficacy in all antinociception tests. In addition, while 57B, compared to clinical opioids, showed a superior recovery of motor coordination after regaining of righting reflex from full anesthetic doses in the rat rotorod test, 57A showed significantly less depression of cardiovascular function at supraanalgesic doses in the isoflurane-anesthetized rat.

Site-Specific Effects of the Nonsteroidal Anti-Inflammatory Drug Lysine Clonixinate on Rat Brain Opioid Receptors

“…The pellet was washed twice by Ortí/Coirini/Pico resuspending and centrifugation. The final pellet was resuspended in 2 ml of 50 mmol/l Tris per gram of starting tissue [28,29]. Aliquots of 2 ml of suspension were frozen at -70°C until used.…”

“…The incubation was stopped by addition of 4 ml ice-cold 50 mmol/l Tris and vacuumfiltration on Whatman GF/C glass fiber filters previously soaked in 0.1% polyethyleneimine. The filters were then washed twice with 4 ml of 50 mmol/l Tris buffer and the radioactivity determined by liquid scintillation [28][29][30][31].…”

Characterization of opiates, neuroleptics, and synthetic analogs at ORL1 and opioid receptors

“…This is further corroborated by the lack of μ affinity of analogs containing constrained or bicyclic N-1 substituents (Bagley et al, 1991). Therefore, anilidopiperidine-based ORL1 receptor ligands that have large lipophilic N-1 piperidine substituents will be inherently selective for ORL1 versus μ and other opioid receptors.…”

A Theoretical Study on the Tautomerism of C-Carboxylic and Methoxycarbonyl Substituted Azoles

“…The diester 40 and its ethyl analog are well known compounds [27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43]. The X-ray structure of the diethyl 1H-pyrazole-3,5-dicarboxylate has been determined [44].…”