The history and development of the fentanyl series

Abstract

In the last two decades, opioid analgesics have assumed an important place in general anesthetic practice in the United States. Part of the reason for this has been the introduction of the potent new agonists fentanyl, sufentanil, and alfentanil. Because of problems with morphine-oxygen anesthesia (incomplete amnesia, occasional histamine-related reaction, marked increases in intra- and postoperative respiratory depression), a suitable alternative was sought but not found among existing opioids. A breakthrough came in 1960, when fentanyl was synthesized, laying the foundation for a better understanding of the structure-activity relationships of narcotic analgesics and stimulating interest in developing compounds with even greater potency and safety margins. Investigators interested in opioid anesthesia began to study fentanyl in animals and then in humans. Fentanyl (50-100 micrograms/kg) with oxygen (100%) was evaluated as an anesthetic in patients undergoing mitral valve and coronary artery surgery. Changes in cardiovascular dynamics with induction doses ranging from 8 to 30 micrograms/kg consisted of small decreases in heart rate and arterial blood pressure. All other cardiovascular variables studied, including cardiac output, remained unchanged, even with additional doses up to 100 micrograms/kg. It was determined that fentanyl had use as a narcotic anesthetic, despite its potential for cardiovascular depression and stimulation, respiratory depression, muscle rigidity, and, occasionally, incomplete anesthesia. Since the introduction of fentanyl, two other potent synthetic opioids have been introduced into clinical practice--sufentanil and alfentanil.

Slow Photoelectron Spectroscopy of δ‐Valerolactam and Its Dimer

“…[ 2 + doublets located in the 0-5 eV internal energy domain. For the monomer, the best compromise (calculation costs and accuracy) is for an active space comprising all the molecular orbitals (MOs) from HOMO-16 to LUMO + 3 as active (HOMO: highest occupied molecular orbital; LUMO: lowest unoccupied molecular orbital).…”

“…The lower panel in Figure 4 displays the one-dimensional evolution of these electronic states along the normal coordinate relative to the out-of-plane torsion 41 mode (Table 3). Figure 4 shows that the ground electronic stateX 2 A and the first excited stateà 2 A become close to each other for q~1908 and Dt~148 where one can see an avoided crossing along the corresponding coordinates. At these nuclear configurations, both electronic states are coupled vibronically and their electronic wavefunctions are strongly mixed (multiconfigurational nature).…”

“…fentanyl). [2] Finally, the cyclic lactam dimers, which are formed by hydrogen bonding, represent simple models for the hydrogen bonding peptide linkage, which participates into the 3D structural properties of large peptides and proteins. In addition, there are structural similarities between d-valerolactam (saturated CC bonds) and 2-pyridone (aromatic six-ring cycle) and dimer, which is considered as a simple model for studying the pairing (hydrogen bonding) between DNA basis pairs.…”

“…These spectra are assigned with the help of theoretical calculations dealing with the equilibrium geometries, electronic-state patterns and evolutions, harmonic and anharmonic wavenumbers of the monomer and dimer, either neutral or positively charged. The state energies of the [d-valerolactam] + cation in theX ground,Ã,B andC excited electronic states, and of the [d-valerolactam] 2 + cation's lowest states are determined. After its formation, [d-valerolactam] 2 + is subject to intramolecular isomerization, H transfer and then unimolecular fragmentation processes.…”

“…The state energies of the [d-valerolactam] + cation in theX ground,Ã,B andC excited electronic states, and of the [d-valerolactam] 2 + cation's lowest states are determined. After its formation, [d-valerolactam] 2 + is subject to intramolecular isomerization, H transfer and then unimolecular fragmentation processes. Close to the ionization thresholds, the photoionization of these molecules is found to be mainly dominated by a direct process whereas the indirect route (autoionization) contributes at higher energies.…”