Allosteric modifiers of hemoglobin: 2-[4-[[(3,5-disubstituted anilino)carbonyl]methyl]phenoxy]-2-methylpropionic acid derivatives that lower the oxygen affinity of hemoglobin in red cell suspensions, in whole blood, and in vivo in rats

Abstract

Two new potent allosteric effectors of hemoglobin, RSR-4 [2-[4-[[(3,5-dichloroanilino)carbonyl]-methyl]phenoxy]-2- methylpropionic acid] and RSR-13 [2-[4-[[(3,5-dimethlanilino)carbonyl]methyl]-phenoxy]-2-methylp rop ionic, are compared to the previously reported compounds L3,5 and L3,4,5 [Lalezari, I., Lalezari, P., Poyart, C., Marden, M., Kister, J., Bohn, B., Fermi, G., & Perutz, M. F. (1990) Biochemistry 29, 1515]. Unlike L3,5 and L3,4,5, RSR-4 and RSR-13 are less impeded by physiological concentrations of serum albumin. RSR-4 has also been shown to be more effective than L3,5 in shifting the allosteric equilibrium of bovine Hb toward the low-affinity T-state. X-ray crystal studies show that both RSR-4 and RSR-13 bind to only one pair of symmetry-related sites in the Hb central water cavity whereas previous studies on L3,5 and L3,4,5 demonstrated a second pair of symmetry-related binding sites near Arg 104 beta. Three major interactions between these allosteric effectors and Hb include the acid group with the guanidinium group of C-terminal Arg 141 alpha, the effector's amide oxygen with the ammonium ion of Lys 99 alpha, and the phi electrons of the halogenated or methylated aromatic ring and Asn 108 beta. No explanation has been found for the difference in number of binding sites observed for RSR-4 and RSR-13 (two sites) compared to L3,5 and L3,4,5 (four sites); also no correlation has been made between the number of binding sites and degree of allosteric shift in the oxygen equilibrium curve.(ABSTRACT TRUNCATED AT 250 WORDS)

Preservation of canine myocardial high-energy phosphates during low-flow ischemia with modification of hemoglobin–oxygen affinity

“…A rightward shift in the Hb-O 2 dissociation curve is observed in patients with angina, congestive heart failure with shock, and acute myocardial infarction, and is believed to be an adaptive response that increases myocardial oxygen delivery (7)(8)(9)(10)(11)(12)(13). Clofibrate and some other synthetic compounds also modestly alter the affinity of hemogloPreservation of canine myocardial high-energy phosphates during low-flow ischemia with modification of hemoglobin-oxygen affinity bin for oxygen (14)(15)(16)(17)(18) (19,20). Although theoretically attractive, the acute effects of a relatively rapid and significant shift in the Hb-O 2 curve on the severity of myocardial ischemia are unknown.…”

RSR13, a Synthetic Allosteric Modifier of Hemoglobin, Improves Myocardial Recovery Following Hypothermic Cardiopulmonary Bypass

“…RSR13, 2-[4-[[(3,5-dimethylanilino carbonyl] methyl]phenoxy]-2-methylpropionic acid, a synthetic allosteric modifier of Hb, has been shown to promote the dissociation of oxygen from Hb, even under hypothermic conditions where oxygen delivery is compromised. [1][2][3][4][5]25 Theoretically, improved myocyte oxygenation by RSR13 during ischemia could improve mechanical recovery during surgical procedures requiring the use of hypothermic cardioplegia. In this study, a canine model of cardiopulmonary bypass was used to examine the ability of RSR13 to enhance functional and metabolic recovery and preserved tissue morphology compared with non-RSR13 supplemented cardioplegia.…”

“…[1][2][3] RSR13 acts to decrease Hb oxygen affinity through stabilization of deoxyHb in a manner similar to the natural allosteric effector of Hb, 2,3-diphosphoglycerate. 4,5 Of additional importance is the ability of RSR13 to reverse the hypothermia-dependent increase in Hb oxygen affinity.…”

Pharmacological correction of hypothermic P50shift does not alter outcome from focal cerebral ischemia in rats

“…Seven days after ischemia, rats underwent a standardized neurological examination designed to evaluate sensorimotor function (1). With the observer blinded to group assignment, this test examined six different functions (spontaneous activity over 5 min, movement symmetry, forepaw outstretching, climbing, body proprioception, and response to vibrissae touch).…”

“…2- carbonyl]methyl]phenoxy]-2-methylproprionic acid (RSR13) belongs to a unique class of synthetic compounds that allosterically modify Hb (1). RSR13 binds to a specific site in the central water cavity of deoxyhemoglobin, reducing Hb O 2 -binding affinity.…”