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Pharmacological characterization of enantiomers of 8‐thiomethyl‐2‐(di‐n‐propylamino)tetralin, potent and selective 5‐HT 1A receptor agonists
Author(s) -
Foreman Mark M.,
Fuller Ray W.,
Leander J. David,
Nelson David L.,
Calligaro David O.,
Lucaites Virginia L.,
Wong David T.,
Zhang L.,
Barrett James E.,
Schaus John M.
Publication year - 1995
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.430340110
Subject(s) - agonist , intrinsic activity , chemistry , endocrinology , partial agonist , medicine , pharmacology , receptor , 5 ht1a receptor , enantiomer , in vivo , potency , serotonin agonist , serotonin , 5 ht receptor , biology , in vitro , stereochemistry , biochemistry , microbiology and biotechnology
LY274600 and LY274601 are the S (−) and R (+) enantiomers, respectively, of 8‐thiomethyl‐2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT). In in vitro studies, both enantiomers have high and selective affinity for the 5‐HT 1A receptor. However, LY274600 produced submaximal inhibition of forskolin‐stimulated cyclase activity, which indicates that it is a partial agonist, whereas LY274601 produced maximal inhibition of cyclase activity, which indicates that it is a full agonist in this model. Both of these enantiomers had potent in vivo pharmacological effects in rats that are characteristic of 5‐HT 1A receptor agonists including (1) a reduction of hypothalamic 5‐HIAA levels, (2) an increase in serum corticosterone levels, (3) a reduction in hypothalamic 5‐HTP accumulation after decarboxylase inhibition, (4) an induction of 5‐HT 1A behavioral responses, e.g., flat posture and lower lip retraction, and (5) a lowering of body temperature. In these general pharmacological tests, both compounds had a potency equal to or greater than 8‐OH‐DPAT but had a greater oral activity. LY274601 appeared to be either slightly more potent or efficacious than LY274600. In the drug‐discrimination studies using pigeons trained to identify the effects of 8‐OH‐DPAT, LY274601 was significantly more potent than LY274600, but both were less potent than 8‐OH‐DPAT. Both enantiomers restored full sexual reflex function to rats that had reduced sexual capacity. In rats with normal capacity for sexual reflexes but reduced performance, the enantiomers caused decreases in ejaculatory latencies and postejaculatory latencies and increases in copulatory efficiency and rate. No consistent differences between the enantiomers could be demonstrated in these estimates of total sexual performance, erectile capacity, and sexual drive. Both enantiomers increased punished responding at lower doses than were needed to decrease unpunished responding in pigeons, an effect that is indicative of anxiolytic activity. LY274600, a partial agonist, produced a significantly greater change in punished responding than did LY274601, a full agonist. Both compounds induced dose‐related decreases in immobility time and defecation rate in the rat forced swim model, which represent reductions in stress‐induced “behavioral despair” and stress‐induced gastrointestinal motility. Collectively, these pharmacological studies have shown that the substitution of a thiomethyl for hydroxyl group at the 8 position on the 2‐(di‐n‐propylamino) tetralin structure resulted in selective and potent agonists for the 5‐HT 1A receptor similar to that of 8‐OH‐DPAT but with improved oral potency. The preclinical efficacy studies demonstrated possible utilites for these compounds in the treatement of either sexual response disorders, anxiety, or depression. © 1995 Wiley‐Liss, Inc.