Structural modifications of the serotonin 5-HT7 receptor agonist N-(4-cyanophenylmethyl)-4-(2-biphenyl)-1-piperazinehexanamide (LP-211) to improve in vitro microsomal stability: A case study.
The 5-HT7 serotonin receptor is revealing a promising target for innovative therapeutic strategies of neurodevelopmental and neuropsychiatric disorders. Here, we report the synthesis of thirty long-chain arylpiperazine analogs of the selective and brain penetrant 5-HT7 receptor agonist LP-211 (1) designed to enhance stability towards microsomal oxidative metabolism. Commonly used medicinal chemistry strategies were used (i.e., reduction of overall lipophilicity, introduction of electron-withdrawing groups, blocking of potential vulnerable sites of metabolism), and in vitro microsomal stability was tested. The data showed that the adopted design strategy does not directly translate into improvements in stability. Instead, the metabolic stability of the compounds was related to the presence of specific substituents in well-defined regions of the molecule. The collected data allowed for the construction of a machine learning model that, in a given chemical space, is able to describe and quantitatively predict the metabolic stability of the compounds. The majority of the synthesized compounds maintained high affinity for 5-HT7 receptors and showed selectivity towards 5-HT6 and dopamine D2 receptors and different selectivity for 5-HT1A and α1 adrenergic receptors. Compound 50 showed 3-fold higher in vitro stability towards oxidative metabolism than 1 and was able to stimulate neurite outgrowth in neuronal primary cultures through the 5-HT7 receptor in a shorter time and at a lower concentration than the agonist 1. A preliminary disposition study in mice revealed that compound 50 was metabolically stable and was able to pass the blood-brain barrier, thus representing a new tool for studying the pharmacotherapeutic potential of 5-HT7 receptor in vivo.
Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari "A. Moro", via Orabona, 4, 70125, Bari, Italy.
Enza
E
Lacivita
Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343, Kraków, Poland; Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060, Kraków, Poland.
Sabina
S
Podlewska
Institute of Genetics and Biophysics "Adriano Buzzati Traverso", CNR, Via P. Castellino 111, 80131, Naples, Italy.
Luisa
L
Speranza
Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari "A. Moro", via Orabona, 4, 70125, Bari, Italy.
Mauro
M
Niso
Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343, Kraków, Poland.
Grzegorz
G
Satała
Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari "A. Moro", via Orabona, 4, 70125, Bari, Italy.
Roberto
R
Perrone
Institute of Genetics and Biophysics "Adriano Buzzati Traverso", CNR, Via P. Castellino 111, 80131, Naples, Italy; Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, 8013, Naples, Italy.
Carla
C
Perrone-Capano
Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343, Kraków, Poland.
Andrzej J
AJ
Bojarski
Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari "A. Moro", via Orabona, 4, 70125, Bari, Italy. Electronic address: marcello.leopoldo@uniba.it.
Marcello
M
Leopoldo
D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D015195:Drug Design; D004355:Drug Stability; D051379:Mice; D008861:Microsomes / Q000378:metabolism; D010879:Piperazines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D011985:Receptors, Serotonin / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000493:pharmacokinetics*
C573815:N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide; D010879:Piperazines; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; C104425:serotonin 7 receptor
5-HT(7) receptor; Arylpiperazine; Machine learning; Microsomal stability; Neurite outgrowth